CNS Stimulants Joseph De Soto MD, PhD, FAIC

Overview Psychomotor stimulants and hallucinogens act on the central nervous system. The psychomotor stimulants cause excitement and euphoria, decrease feelings of fatigue, and increase motor activity. The hallucinogens produce profound changes in thought patterns and mood with little effect on the brainstem and spinal cord. Reticular formation: is a set of interconnected nuclei that are located throughout the brainstem and is divided into three raphe nuclei (median), magnocellular red nucleus (medial zone), and parvocellular reticular nucleus (lateral zone). The reticular formation regulates levels of consciousness.

Psychomotor Stimulants Caffeine Methylxanthines: include theophylline which is found in tea, theobromine found in cocoa, and caffeine found in coffee, and tea cocoa, chocolate and certain sodas. The methylxanthines work by: 1.competitive nonselective phosphodiesterase inhibitors which raise intracellular cAMP, activate PKA. 2.As nonselective adenosine receptor antagonists which inhibit sleep inducing adenosine. 3. Inhibiting TNF-α and leukotriene synthesis, and reduce inflammation and innate immunity.

Psychomotor Stimulants Caffeine CNS: the caffeine contained in two cups of coffee 100 to 200 mg causes a decrease in fatigue and an increase in the mental alertness by stimulating the brain. Tolerance can develop rapidly to the stimulating properties leading to withdrawal symptoms of fatigue and sedation. Cardiovascular system: a high dose of caffeine leads to inotropic and chronotropic effects. Pulmonary system: a high dose results in mild to moderate bronchodilation.

Psychomotor Stimulants Caffeine Therapeutic use: the methylxanthine theophylline has been used to dilate the smooth muscles of the bronchioles for treatment of asthma. Caffeine is at times is added to acetaminophen and aspirin for headaches. Pharmacokinetics: Methylxanthines are well absorbed and distribute through the body inclusive of the CNS. They are metabolized by CYP1A2 and the metabolites excreted in the urine. Half life of caffeine 3-7 hours. Adverse effects: withdrawal symptoms in those who drink six cups of coffee or more and who stop.

Psychomotor Stimulants Nicotine Nicotine: is the active ingredient in tobacco and it is second to caffeine as the most widely used stimulant. At low doses nicotine causes ganglionic stimulation by depolarization of the N N receptors. At high doses nicotine causes depolarizing blockade of the N N receptors. CNS: nicotine is lipid soluble and easily gets into the CNS. At low doses there is mild euphoria and relaxation. This improves learning, problem solving, and reaction time. High doses of nicotine results in respiratory depression and severe hypertension. Nicotine is an appetite suppressant.

Psychomotor Stimulants Nicotine Peripheral effects: stimulation of the sympathetic ganglia and the adrenal medulla increases blood pressure and heart rate. Those with peripheral vascular disease experience an exacerbation of symptoms with smoking. Indeed, vasoconstriction with nicotine can decrease coronary artery flow. Stimulation of the sympathetic ganglia increases the activity of the bowel. At higher doses blood pressure falls, breathing slows, and the gastrointestinal tract slows due to blockage of the ganglia.

Psychomotor Stimulants Nicotine Pharmacokinetics: More than 90% of nicotine in smoke is absorbed by the body. Clearance of nicotine involves metabolism by the lung, liver and by urinary excretion. Adverse effects of nicotine: irritability, and tremors. Adverse effects of smoking: Increased risk for cancer, reduced fertility and accelerated atherosclerosis. Withdrawal syndrome: nicotine is addictive and physical dependence occurs rapidly and can be severe. Symptoms include irritability, anxiety, restlessness, difficulty concentrating, headaches and insomnia.

Psychomotor Stimulants Varenicline Varenicline: is a partial agonists at neuronal nicotinic receptors. This medication produces a small euphoric effect less intense than nicotine. Hence, it is used as a adjunct to help patients stop smoking. It attenuates the feeling of pleasure when a person smokes, This drug is also useful for withdrawal symptoms. Adverse effects: suicidal thoughts, vivid nightmares, and mood changes.

Psychomotor Stimulants Amphetamines Let’s review the effects of the Amphetamines. Recall, that amphetamine blocks the vesicular monoamine transporter 2 which blocks the storage of amphetamine in the vesicles of the neuron. Thus, catecholamine's will begin to be released from the neuronal ends. So, much is released that not all the catecholamine's can be reabsorbed in the synaptic cleft. Amphetamine may also inhibit MAO

Psychomotor Stimulants Amphetamines CNS: amphetamine stimulates the entire cerebrospinal axis, cortex, brainstem, and medulla. This leads to increased alertness, decreased appetite, and insomnia. At high doses psychosis and convulsion can occur. Pharmacokinetics: amphetamine is completely absorbed from the GI tract, metabolized by the liver, and its metabolites excreted in the urine. Amphetamine abusers often administer the drugs by IV or by smoking. The euphoria, caused by amphetamine lasts 4 to 6 hours much longer than the effects of cocaine, though the intensity of the maximum euphoria is lower.

Psychomotor Stimulants Amphetamines Therapeutic uses: psychological and physical dependence with chronic use and the development of tolerance limit the use of these medications. Adverse effects: insomnia, weakness, dizziness, tremor, and hyper- reactive reflexes, hypertension, psychosis, cardiac arrhythmias, and sweating. In those who are mentally they are at elevated risk for confusion, delirium, panic states, and suicide.

Psychomotor Stimulants Narcolepsy: this is a sleep disorder characterized by uncontrollable bouts of sleepiness during the day. It may also be accompanied by catalepsy or paralysis. It may be caused in part by autoimmunity against also called hypocretin, is a neurotransmitter that regulates arousal, wakefulness, and appetite In those with narcolepsy it may brought about by strong emotion such as laughter or surprise. This disorder can be treated with Modafinil. Modafinil elevates hypothalamic histamine levels, and inhibits the reuptake action of the dopamine transporter, leading to an increase synaptic concentrations of dopamine. Adverse effects: side effects such as stomach pain, skin irritation, anxiety, and with prolonged use elevated liver enzymes.

Psychomotor Stimulants Attention deficit hyperactivity disorder: some young children are hyperactive and have difficulty focusing on one activity for more than a few minutes. Dextroamphetamine, methamphetamine, and methylphenidate are used to help improve attention span and to help alleviate some of the behavioral problems. Atomoxetine: is more selective for norepinephrine than dopamine thus, it doesn’t have the same addiction potential.

Psychomotor Stimulants Methylphenidate: this is one of the most prescribed medications in children and many children take this medication daily for ADHD. This medication is also indicated for narcolepsy. Adverse events: appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia, abdominal pain, akathisia, blurred vision mydriasis, induction of mania for those who are schizoaffective or bipolar. Long term use: psychosis, and decreased growth.