Chapter 10: CNS Stimulants




This chapter describes two groups of drugs that act primarily to stimulate the central nervous system (CNS). The first group, the psychomotor stimulants, cause excitement and euphoria, decrease feelings of fatigue, and increase motor activity. The second group, the hallucinogens, or psychotomimetic drugs, produce profound changes in thought patterns and mood, with little effect on the brainstem and spinal cord. Figure 10.1 summarizes the CNS stimulants. As a group, the CNS stimulants have diverse clinical uses and are important as drugs of abuse, as are the CNS depressants described in Chapter 9 and the narcotics described in Chapter 14 (Figure 10.2).

Figure 10.1.Summary of central nervous system (CNS) stimulants.

Summary of central nervous system (CNS) stimulants.

Figure 10.2.Relative potential for physical dependence on commonly abused substances.

Relative potential for physical dependence on commonly abused substances.

LSD = lysergic acid diethylamide.

Psychomotor Stimulants

A. Methylxanthines

The methylxanthines include theophylline [thee-OFF-i-lin], which is found in tea; theobromine [thee-o-BRO-min], found in cocoa; and caffeine [kaf-EEN]. 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.

1. Mechanism of action

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.

2. Actions

a. CNS

The caffeine contained in one to two cups of coffee (100–200 mg) 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 (2–5 g) of caffeine. Tolerance can rapidly develop to the stimulating properties of caffeine, and withdrawal consists of feelings of fatigue and sedation.

b. Cardiovascular system

A high dose of caffeine has positive inotropic and chronotropic effects on the heart. [Note: Increased contractility can be harmful to patients with angina pectoris. In others, an accelerated heart rate can trigger premature ventricular contractions.]

c. Diuretic action

Caffeine has a mild diuretic action that increases urinary output of sodium, chloride, and potassium.

d. Gastric mucosa

Because all methylxanthines stimulate secretion of hydrochloric acid from the gastric mucosa, individuals with peptic ulcers should avoid foods and beverages containing methylxanthines.

3. Therapeutic uses

Caffeine and its derivatives relax the smooth muscles of the bronchioles. [Note: Previously the mainstay of asthma therapy, theophylline has been largely replaced by other agents, such as ?2 agonists and corticosteroids.]

4. Pharmacokinetics

The methylxanthines are well absorbed orally. Caffeine distributes throughout the body, including the brain. These drugs cross the placenta to the fetus and are secreted into the mother’s milk. All the methylxanthines are metabolized in the liver, generally by the CYP1A2 pathway, and the metabolites are then excreted in the urine.

5. 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 consumed more than 600 mg of caffeine per day (roughly six cups of coffee per day) and then suddenly stop.

B. Nicotine

Nicotine [NIK-o-teen] is the active ingredient in tobacco. Although this drug is not currently used therapeutically (except in smoking cessation therapy), nicotine remains important because it is second only to caffeine as the most widely used CNS stimulant, and it is 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, and other illnesses. Dependency on the drug is not easily overcome.

1. Mechanism of action

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.

2. Actions

a. CNS

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 and severe hypotension caused by medullary paralysis (Figure 10.3). Nicotine is also an appetite suppressant.

Figure 10.3.Actions of nicotine on the central nervous system.

Actions of nicotine on the central nervous system.

b. Peripheral effects

The peripheral effects of nicotine are complex. Stimulation of sympathetic ganglia as well as the adrenal medulla increases blood pressure and heart rate. Thus, use of tobacco is particularly harmful in hypertensive patients. Many patients with peripheral vascular disease experience an exacerbation of symptoms with smoking. For example, nicotine-induced vasoconstriction can decreased coronary blood flow, adversely affecting a patient with angina. Stimulation of parasympathetic ganglia also increases motor activity of the bowel. At higher doses, blood pressure falls, and activity ceases in both the gastrointestinal (GI) tract and bladder musculature as a result of a nicotine-induced block of parasympathetic ganglia.

3. Pharmacokinetics

Because nicotine is highly lipid soluble, absorption readily occurs via the oral mucosa, lungs, GI 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. 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 after beginning usage.

4. Adverse effects

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 for a number of drugs.

5. Withdrawal syndrome

As with the other drugs in this class, nicotine is an addictive substance, and physical dependence develops rapidly and can be severe (Figure 10.4). Withdrawal is characterized by irritability, anxiety, restlessness, difficulty concentrating, headaches, and insomnia. Appetite is affected, and GI pain often occurs. [Note: Smoking cessation programs that combine pharmacologic and behavioral therapy are the most successful in helping individuals to stop smoking.]

The transdermal patch and chewing gum containing nicotine have been shown to reduce nicotine withdrawal symptoms and to help smokers stop smoking. For example, the blood concentration of nicotine obtained from nicotine chewing gum is typically about one-half the peak level observed with smoking (Figure 10.5). Bupropion, an antidepressant (see Atypical Antidepressants), can reduce the craving for cigarettes.

Figure 10.4.Nicotine has potential for addiction.

Nicotine has potential for addiction.

Figure 10.5.Blood concentrations of nicotine in individuals who smoked cigarettes, chewed nicotine gum, or received nicotine by transdermal patch.

Blood concentrations of nicotine in individuals who smoked cigarettes, chewed nicotine gum, or received nicotine by transdermal patch.

C. Varenicline

Varenicline [ver-EN-ih-kleen] is a partial agonist at neuronal nicotinic acetylcholine receptors in the CNS. Because varenicline is only a partial agonist at these receptors, it produces less euphoric effects than those produced by nicotine itself (nicotine is a full agonist at these receptors). Thus, it is useful as an adjunct in the management of smoking cessation in patients with nicotine withdrawal symptoms. Additionally, varenicline tends to attenuate the rewarding effects of nicotine if a person relapses and uses tobacco. Patients should be monitored for suicidal thoughts, vivid nightmares, and mood changes.

D. Cocaine

Cocaine [KOE-kane] is a widely available and highly addictive drug that is currently abused daily by more than 3 million people in the United States. Because of its abuse potential, cocaine is classified as a Schedule II drug by the U.S. Drug Enforcement Agency.

1. Mechanism of action

The primary mechanism of action underlying the central and peripheral effects of cocaine is blockade of reuptake of the monoamines (norepinephrine, serotonin, and dopamine) into the presynaptic terminals from which these neurotransmitters are released (Figure 10.6). This blockade is caused by cocaine binding to the monoaminergic reuptake transporters, and, thus, potentiates and prolongs the CNS and peripheral actions of these monoamines. In particular, the prolongation of dopaminergic effects in the brain’s pleasure system (limbic system) produces the intense euphoria that cocaine initially causes. Chronic intake of cocaine depletes dopamine. This depletion triggers the vicious cycle of craving for cocaine that temporarily relieves severe depression (Figure 10.7).

Figure 10.6.Mechanism of action of cocaine.

Mechanism of action of cocaine.

Figure 10.7.Cocaine and amphetamine have potential for addiction.

Cocaine and amphetamine have potential for addiction.

2. Actions

a. CNS

The behavioral effects of cocaine result from powerful stimulation of the cortex and brainstem. Cocaine acutely increases mental awareness and produces a feeling of wellbeing and euphoria similar to that caused by amphetamine. Like amphetamine, cocaine can produce hallucinations and delusions of paranoia or grandiosity. Cocaine increases motor activity, and, at high doses, it causes tremors and convulsions, followed by respiratory and vasomotor depression.

b. Sympathetic nervous system

Peripherally, cocaine potentiates the action of norepinephrine, and it produces the “fight-or-flight” syndrome characteristic of adrenergic stimulation. This is associated with tachycardia, hypertension, pupillary dilation, and peripheral vasoconstriction. Recent evidence suggests that the ability of baroreceptor reflexes to buffer the hypertensive effect may be impaired.

c. Hyperthermia

Cocaine is unique among illicit drugs in that death can result not only as a function of dose, but also from the drug’s propensity to cause hyperthermia. [Note: Mortality rates for cocaine overdose rise in hot weather.] Even a small dose of intranasal cocaine impairs sweating and cutaneous vasodilation. Perception of thermal discomfort is also decreased.

3. Therapeutic uses

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. [Note: Cocaine is the only local anesthetic that causes vasoconstriction. This effect is responsible for the necrosis and perforation of the nasal septum seen in association with chronic inhalation of cocaine powder.]

4. Pharmacokinetics

Cocaine is often self-administered by chewing, intranasal snorting, smoking, or intravenous (IV) injection. The peak effect occurs 15 to 20 minutes after intranasal intake of cocaine powder, and the “high” disappears in 1 to 1.5 hours. Rapid but short-lived effects are achieved following IV injection of cocaine or by smoking the freebase form of the drug (“crack”). Because the onset of action is most rapid, the potential for overdosage and dependence is greatest with IV injection and crack smoking. Cocaine is rapidly de-esterified and demethylated to benzoylecgonine, which is excreted in the urine. Detection of this substance in the urine identifies a user.

5. Adverse effects

a. Anxiety

The toxic response to acute cocaine ingestion can precipitate an anxiety reaction that includes hypertension, tachycardia, sweating, and paranoia. [Note: Little tolerance to the toxic CNS effects of cocaine (for example, convulsions) occurs with prolonged use.] Because of the irritability, many users take cocaine with alcohol. A product of cocaine metabolites and ethanol is cocaethylene, which is also psychoactive and believed to contribute to cardiotoxicity.

b. Depression

As with all stimulant drugs, cocaine stimulation of the CNS is followed by a period of mental depression. Addicts withdrawing from cocaine exhibit physical and emotional depression as well as agitation. The latter symptom can be treated with benzodiazepines or phenothiazines.

c. Toxic effects

Cocaine can induce seizures as well as fatal cardiac arrhythmias (Figure 10.8). Use of IV diazepam may be required to control cocaine-induced seizures. The incidence of myocardial infarction in cocaine users is unrelated to dose, to duration of use, or to route of administration. There is no marker to identify those individuals who may have life-threatening cardiac effects after taking cocaine.

Figure 10.8.Major effects of cocaine use.

Major effects of cocaine use.