Clinical pharmacology of psychostimulants
Pharmacodynamic classification of psychostimulants
Indirect adrenomimetics increase the release of endogenous catecholamines from presynaptic depots, inhibit the reuptake of mediators and increase their concentration in the synaptic cleft.
Phenylalkylamine derivatives
Phenamine (amphetamine, benzedrine) is the most active psychostimulant. It enhances the activity of the adrenergic system (activation of glycogenolysis and lipolysis), promotes the mobilization, delivery and utilization of energy resources necessary to improve the body’s performance. However, the use of energy resources is not economical and leads to an increase in the body’s oxygen demand, which is covered by strengthening the work of the respiratory and cardiovascular systems. Against the background of taking phenamine, tachycardia and increased blood pressure may develop. By influencing the food center of the hypothalamus, it suppresses hunger. Due to the depletion of the body’s energy resources, after taking the drug, there is a period of aftereffect (increased fatigue, lethargy, drowsiness), which can last 1-3 days. Taking phenamine causes euphoria, which is the basis for the development of mental addiction to the drug. The use of this psychostimulant is limited to a small range of therapeutic effects. Pervitin (methamphetamine) is similar to phenamine in all respects.
Pyridine derivatives
The main representative of this group of drugs is meridil. It has a less strong stimulating and euphoric effect and has less effect on peripheral adrenergic structures than phenamine. Meridil is similar in pharmacological effects to pyridrol and centedrine.
Derivatives of sydnonyms
Drugs of this group have a fairly pronounced but lower psychostimulating activity compared to amphetamine, while at the same time they have a less drastic negative effect on the vegetative functions of the body. The main representative of this group of drugs in our country is sidnocarb (mesocarb). Sydnocarb acts primarily on the noradrenergic systems of the brain. The stimulating effect of the drug develops gradually and persists for a long time. Sydnocarb does not cause a pronounced peripheral sympathomimetic effect. In structure and effect, sydnocarb is similar to syndophene, but it acts more weakly.
Adenosine receptor blockers (adenosinolytics)
By blocking inhibitory adenosine receptors in the central nervous system, they lead to increased activity of the cortex and subcortical structures.
Derivatives of methylxanthines
The alkaloids caffeine, theobromine, and theophylline belong to methylxanthines. Caffeine has the strongest effect on the central nervous system. Caffeine is an alkaloid found in tea and coffee. Its stimulating effect on the central nervous system leads to an increase in mental and physical performance, a decrease in fatigue and drowsiness. It weakens the effect of hypnotics and narcotic drugs, increases the reflex excitability of the spinal cord, and stimulates the respiratory and vasomotor centers. In a collaptoid state, it increases blood pressure.
Clinical pharmacokinetics of psychostimulants
Amphetamine is rapidly absorbed from the gastrointestinal tract and evenly distributed in various body tissues, easily penetrating through the BBB due to its high lipophilicity. The peak concentration in the blood and the main clinical effects occur 30-60 minutes after taking the drug. Amphetamine is not metabolized in the liver and is excreted unchanged in the urine. T1/2 depends on the pH of urine: at a pH below 5.6, it is about 7 hours, and at a pH above 7.1–8.0, it can increase to 30 hours. An increase in pH by 1.0 increases T1/2 by about 7 hours, which is associated with increased reabsorption of the drug. On average, T1/2 of amphetamine is about 12 hours.
Caffeine is rapidly absorbed into the digestive tract. As the pH of the gastric contents increases, the absorption of the drug in the stomach increases. The peak concentration in the blood occurs approximately 1 hour after ingestion. Due to its high lipophilicity, caffeine easily penetrates through the BBB and is evenly distributed in body tissues. Only 15-30% of the dose binds to blood proteins. Most of the caffeine is metabolized in the liver by oxidation and demethylation and is excreted in the urine (about 1% unchanged). T1/2 varies between 2.5–12 hours (on average 3-7 hours).
Caffeine easily penetrates the placenta and reaches concentrations in the fetal blood and tissues close to those in the mother’s body. Taking large amounts of products containing caffeine can increase the risk of spontaneous abortions or delayed fetal development, as well as lead to fetal arrhythmias. Therefore, pregnant women are not recommended to take more than 300 mg of caffeine (3 cups of coffee) per day. Caffeine penetrates into breast milk in very small amounts.
Indications for use
In healthy people, psychostimulants are used to overcome fatigue, drowsiness, and temporarily increase physical and mental performance. Drugs of this class are effective in transient asthenic conditions, shallow cognitive disorders accompanied by attention deficit, and in the treatment of depression (in combination with antidepressants).
Amphetamines are prescribed as a short course for severe asthenic conditions and narcolepsy, attention deficit hyperactivity disorder in children.
Sydnonymines are indicated in all variants of asthenic conditions occurring with: inhibition,
drowsiness,
lethargy,
apathy,
decreased working capacity,
as well as narcolepsy.
Caffeine is usually used as a mild stimulant of the central nervous system in order to maintain mental performance and wakefulness during fatigue and drowsiness.
As an auxiliary agent, caffeine is used:
for sleep apnea in newborns,
to enhance the effect of electroconvulsive therapy, treatment of vascular headaches (in combination with ergotamine),
with analgesic therapy in combination with acetaminophen (paracetamol) or acetylsalicylic acid.
Side effects
With prolonged use, psychostimulants can lead to the development of addiction. Somatic side effects of drugs include:
arrhythmias,
irritability,
agitation, insomnia,
eye accommodation disorders,
constipation,
loss of appetite,
nausea,
stomach pain,
vomiting,
pain, dryness or an unpleasant taste in the mouth, increased sweating,
allergic reactions (skin rash or urticaria),
sore throats,
tics,
motor hyperkinesis,
hyperthermia.
With prolonged use or use of high doses of psychostimulants, cardiomyopathy, increased blood pressure, psychotic reactions or conditions, decreased sexual desire and potency, weight loss, confusion or delirium, increased tactile or pain sensitivity, tremor, muscle twitching may develop.
Drug interaction
When psychostimulants are combined with tricyclic antidepressants (TCAS), sympathomimetic effects may increase, which can lead to the development of arrhythmias, tachycardia, hypertension and hyperthermia.
Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine and selegiline, can prolong and enhance the stimulation of cardiac activity and pressor effects of amphetamines, which is manifested by cardiac arrhythmias, headache, vomiting, hypertensive and hyperpyrexic crises. Therefore, amphetamines should not be prescribed earlier than 14 days after the withdrawal of MAO inhibitors.
The use of sympathomimetics and levodopa in combination with amphetamines can lead to overexcitation of the central nervous system with the development of pronounced psychomotor agitation, insomnia, and sometimes convulsive syndrome, as well as to an increased effect of sympathomimetics on blood vessels and the heart; when combined with cardiac glycosides, the risk of cardiac arrhythmias increases.
Amphetamines can enhance the analgesic effects of meperidine, but it is not recommended to combine these drugs, as hypotension, severe respiratory depression, seizures and hyperthermia are possible.
Amphetamines can increase the side effects of thyroid hormones on the heart. In particular, they increase the risk of developing coronary insufficiency. When used concomitantly with amphetamines, it is possible to slow down the absorption of certain anticonvulsants in the intestine (ethosuximide, phenobarbital and phenytoin). Drugs that increase the acidity of gastric juice (for example, ascorbic acid, glutamic acid), as well as drugs that increase the acidity of urine (for example, ammonium chloride), can reduce the effect of amphetamines due to a decrease in their absorption and acceleration of excretion. Due to secondary anticholinergic effects, amphetamine can enhance the effect of anticholinergic drugs.
The combination of caffeine with other xanthine derivatives (euphyllin, theophylline), as well as with bronchodilators from the group of adrenostimulants may increase the risk of side effects. Cimetidine, macrolides, ciprofloxacin, enoxacin, oral contraceptives, disulfiram reduce the metabolism of caffeine and increase its concentration in the blood. Phenytoin, hexamidine and barbiturates increase the total clearance of caffeine. Co-administration of caffeine with beta-blockers may lead to a mutual weakening of therapeutic effects. Caffeine increases the excretion of lithium from the body and can reduce its concentration in blood plasma.
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