Central nervous system stimulants
Synonyms and keywords:

# Overview
Central Nervous System (CNS) stimulants cross the blood-brain barrier and influence neurotransmission through different mechanisms with resultant sympathomimetic effects. They mainly act on neurotransmitter systems, particularly dopamine, norepinephrine, and serotonin, increasing the release of these neurotransmitters or blocking their reuptake. Psychoactive drugs include mainly cocaine, amphetamine, methamphetamine, and caffeine. 

# Cocaine
Cocaine (benzoylmethylecgonine) is derived from Erythroxylan coca extract, a plant found in Western South America. It exists in two forms: salt form and a free-base form. These formulations are essential as they determine the route of administration whereby the salt form is used via nasal inhalation or injection while the free-base form is administered with smoking. It is used for anesthesia and vasoconstriction in nasal surgery clinically; however, it is more notorious as a commonly abused substance.

## Mechanism of Action
Cocaine inhibits the reuptake of dopamine by binding to the transporter proteins. This inhibition increases the availability of dopamine in the synaptic cleft. This action is responsible for the euphoria in cocaine use. The sympathetic effects of cocaine use are due to the inhibition of norepinephrine reuptake in a similar mechanism as the dopamine reuptake inhibition. The decrease explains the development of tolerance in cocaine use in the number of dopamine receptors in the post-synaptic neuron and subsequent upregulation of dopamine transporters and cocaine receptors to achieve the same euphoric effects.   

## Acute Toxicity
Acute cocaine toxicity is characterized by sympathetic symptoms such as hypertension, hyperthermia, agitation, and seizures. The vasoconstrictive effects of cocaine induce arterial spasm, increased myocardial oxygen demand, and ultimately, myocardial infarction. Cocaine also binds to sodium channels inhibiting depolarization of heart muscles. Cocaine toxicity also causes changes in cardiac architecture mediated by interstitial fibrosis and destruction of myofibrils that may subsequently cause dilated cardiomyopathy. The long-term effects of cocaine on the heart assessed by cardiovascular magnetic resonance.

## Management
Benzodiazepines enhance the inhibitory effects of gamma-aminobutyric acid (GABA), leading to sedation and a decrease in sympathetic outflow. They are used as first-line treatment for cocaine-associated chest pain and myocardial infarction while also addresses agitation. Although, adverse side effects must be considered, such as paradoxical agitation, decreased vagal tone, and increased heart rate.
Calcium channel blockers(CCBs) have also been studied to address increased systemic vascular resistance and coronary vasospasm. However, reflex tachycardia may occur as a side effect. The 2013 ACC/AHA guideline recommends oral CCBs (Class I-C evidence) in treating cocaine-induced chest pain with ST-segment changes. Nitroglycerin and nitroprusside are used to treat cocaine-induced hypertension, coronary artery vasospasm, and chest pain, although the potential for hypotension, reflex tachycardia, and treatment failure must be recognized.
Antipsychotics control agitation and psychosis, and combination treatment with benzodiazepines and antipsychotics are more effective than monotherapy.
Hyperthermia from cocaine toxicity is best treated with external cooling measures such as tepid water misting with convection cooling from a fan. Rapid cooling decreases temperature-induced vasodilation and prevents protein denaturation, and subsequently reduces cardiac output by reducing myocardial oxygen demand.

# Amphetamines
Amphetamines are phenethylamine derivatives that include amphetamine and methamphetamine and MDMA (ecstasy), and MDEA. These drugs have a sympathomimetic activity that is mediated in a variety of ways. Clinically, amphetamine is a recognized drug in the treatment of Attention Deficit Hyperactivity Disorder (ADHD), depression, and narcolepsy.

## Mechanism of Action
Amphetamine exerts its sympathomimetic activity in a variety of ways.This includes the release of the neurotransmitters and reuptake inhibition- dopamine, norepinephrine, or serotonin from nerve terminals, monoamine oxidase(MAO) activity inhibition, or direct action of the receptors of neurotransmitters.  Amphetamines have a similar structure to the neurotransmitters serotonin, dopamine, and norepinephrine; hence, they compete with the reuptake transporters of these neurotransmitters.This process decreases the reuptake of the neurotransmitters, increasing their availability in the synaptic cleft and subsequent sympathomimetic effects, increased alertness, and elevation of mood, making it an effective drug in ADHD and narcolepsy.  

## Adverse Effects
Some of the noted side effects of amphetamine are anxiety, restlessness, dry mouth, tremors, insomnia, anorexia, and weight loss. Nausea, vomiting, abdominal cramps, increased blood pressure and heart rate, and exacerbation of motor tics have also been reported. 

## Acute Toxicity
Cardiovascular and neurologic manifestations dominate the presentation of overdose; however, other life-threatening symptoms may also occur, such as serotonin syndrome, rhabdomyolysis, acute liver failure, hyponatremia, and cerebral edema causing coma. One of the manifestations of serotonin syndrome, hyperthermia, leads to rhabdomyolysis due to inadequate fluid replacement, and subsequent multi-organ failure ensues due to myoglobinuria. The increased temperature in patients also drives them to increase their water intake resulting in fluid overconsumption and dilutional hyponatremia.

## Management
Gastrointestinal decontamination using activated charcoal is used in patients present early after overdose (1-2 hours). However, this should be avoided in cases of decreased mentation. Symptomatic treatment is also administered. 
Severe hyperthermia is treated with aggressive cooling and adequate fluid resuscitation to achieve at least a temperature of 38.8 C. Dantrolene is also administered in unresponsive cases, especially in patients with temperatures above 40 C.
Seizures are managed with benzodiazepines. Diazepam 0.1-0.3 mg/kg IV or per rectal is often used, and unresponsive patients must be intubated and investigated for the underlying cause of seizures. Electrolytes should be checked for hyponatremia and urinalysis to check for [[myoglobin[[, creatine kinase levels, and urine output monitoring should be assessed for rhabdomyolysis.
Sinus tachycardia, the most common ECG abnormality in these patients, usually does not require any intervention. Hypertension and tachycardia usually respond to benzodiazepines. 

# Caffeine
Caffeine belongs to the methylxanthine class and is the most widely available CNS stimulant. It is approved in the treatment of apnea of prematurity and some of its off-label use include treatment of migraine headaches and performance enhancer in endurance sports.  Some of caffeine's effects at an effective dose of 85-200 mg are reduced drowsiness and fatigue, mood elevation, improved alertness, and increased productivity.

## Mechanism of Action
The molecular structure of caffeine, similar to adenosine, allows competitive binding to adenosine receptors leading to inhibition of adenosine, particularly the A2a receptors in the brain, which is responsible for the increased alertness with caffeine intake. Adenosine receptors are also found in cardiac muscles, and inhibition of adenosine A1 receptors has positive inotropic effects. This inhibition also results in the release of catecholamines contributing to increased heart rate.
Another proposed mechanism of caffeine is the mobilization of intracellular calcium from the sarcoplasmic reticulum. This activates the endothelial nitric oxide (eNOS) with resulting increased nitric oxide, subsequently mediating contractility in skeletal muscles.
Lastly, it competitively inhibits phosphodiesterase, which inhibits cyclic adenosine monophosphate degradation (cAMP). However, this mechanism requires high doses of caffeine.

## Toxicity
High levels of caffeine (1.2 g or higher) induce anxiety, restlessness, nervousness, insomnia, and agitation.

# Modafinil
Modafinil (2- acetamide is a non-amphetamine CNS stimulant. It is approved for the treatment of Narcolepsy, Obstructive sleep apnea, and shift work disorder. Off-label use of this drug includes treatment for ADHD, cancer-related fatigue, cocaine dependence, bipolar depressive episodes, and multiple sclerosis-related fatigues."Modafinil - StatPearls - NCBI Bookshelf"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

## Mechanism of Action
While the exact mechanism of how modafinil exerts its actions remain unclear, several studies revealed that it binds to the dopamine transporter in the striatum increasing dopamine levels. It also stimulates glutamate-mediated neural circuits while inhibiting GABA. Indirectly, it also inhibits norepinephrine reuptake and has partial alpha 1-adrenergic agonist properties by direct receptor stimulation. 

## Adverse Effects
Side effects of modafinil are fairly low and the main side effects are nausea and headache while diarrhea, nose and throat congestion, back pain, dry mouth, anxiety, insomnia and dizziness have also been described. The incidence of side effects is attributed to dosage levels whereby decreasing the dose alleviates side effects."Modafinil Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD".