Central nervous system stimulants
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chelsea Mae Nobleza, M.D.[2]
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.[1] [2]
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.[3]
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. [2] [4]
Acute Toxicity
Acute cocaine toxicity is characterized by sympathetic symptoms such as hypertension, hyperthermia, agitation, and seizures.[5] 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.[6] 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.[7]
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.[8] Calcium channel blockers 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 or calcium channel blockers (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.[9] Antipsychotics control agitation and psychosis, and combination treatment with benzodiazepines and antipsychotics are more effective than monotherapy.[10] 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.[2]
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.[2] Clinically, amphetamine is a recognized drug in the treatment of Attention Deficit Hyperactivity Disorder (ADHD), depression, and narcolepsy.[11]
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 activity inhibition, or direct action of the receptors of neurotransmitters. [1] 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.[2] [1] [12]
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.[1] [13]
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 and 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.[14]
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. [14]
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.[15] [16] 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.[1]
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.[17] 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.[18]
Toxicity
High levels of caffeine (1.2 g or higher) induce anxiety, restlessness, nervousness, insomnia, and agitation.[1]
Epidemiology and Demographics
The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.
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In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.
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In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%.
Patients of all age groups may develop [disease name].
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The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.
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[Disease name] commonly affects individuals younger than/older than [number of years] years of age.
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[Chronic disease name] is usually first diagnosed among [age group].
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[Acute disease name] commonly affects [age group].
There is no racial predilection to [disease name].
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[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].
[Disease name] affects men and women equally.
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[Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.
The majority of [disease name] cases are reported in [geographical region].
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[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].
Risk Factors
There are no established risk factors for [disease name].
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The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].
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Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
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Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.
Screening
There is insufficient evidence to recommend routine screening for [disease/malignancy].
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According to the [guideline name], screening for [disease name] is not recommended.
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According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].
Natural History, Complications, and Prognosis
If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
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Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
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Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.
Diagnosis
Diagnostic Study of Choice
The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].
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The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].
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The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].
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There are no established criteria for the diagnosis of [disease name].
History and Symptoms
The majority of patients with [disease name] are asymptomatic.
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The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].
Physical Examination
Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].
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Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].
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The presence of [finding(s)] on physical examination is diagnostic of [disease name].
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The presence of [finding(s)] on physical examination is highly suggestive of [disease name].
Laboratory Findings
An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].
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Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
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[Test] is usually normal among patients with [disease name].
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Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].
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There are no diagnostic laboratory findings associated with [disease name].
Electrocardiogram
There are no ECG findings associated with [disease name].
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An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
X-ray
There are no x-ray findings associated with [disease name].
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An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
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There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with [disease name].
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Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
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There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
CT scan
There are no CT scan findings associated with [disease name].
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[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
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There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
MRI
There are no MRI findings associated with [disease name].
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[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
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There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
Other Imaging Findings
There are no other imaging findings associated with [disease name].
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[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
Other Diagnostic Studies
There are no other diagnostic studies associated with [disease name].
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[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
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Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].
Treatment
Medical Therapy
There is no treatment for [disease name]; the mainstay of therapy is supportive care.
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Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].
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The majority of cases of [disease name] are self-limited and require only supportive care.
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[Disease name] is a medical emergency and requires prompt treatment.
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The mainstay of treatment for [disease name] is [therapy].
OR The optimal therapy for [malignancy name] depends on the stage at diagnosis.
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[Therapy] is recommended among all patients who develop [disease name].
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Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].
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Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].
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Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].
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Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].
Surgery
Surgical intervention is not recommended for the management of [disease name].
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Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]
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The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].
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The feasibility of surgery depends on the stage of [malignancy] at diagnosis.
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Surgery is the mainstay of treatment for [disease or malignancy].
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 George, Alan J. (2000). "Central nervous system stimulants". Best Practice & Research Clinical Endocrinology & Metabolism. 14 (1): 79–88. doi:10.1053/beem.2000.0055. ISSN 1521-690X.
- ↑ 2.0 2.1 2.2 2.3 2.4 Kaleta, Erin (2020). "Central nervous system stimulants": 227–238. doi:10.1016/B978-0-12-815846-3.00014-4.
- ↑ Benowitz, Neal L. (1993). "Clinical Pharmacology and Toxicology of Cocaine". Pharmacology & Toxicology. 72 (1): 3–12. doi:10.1111/j.1600-0773.1993.tb01331.x. ISSN 0901-9928.
- ↑ Sofuoglu, Mehmet; Sewell, R. Andrew (2009). "Norepinephrine and stimulant addiction". Addiction Biology. 14 (2): 119–129. doi:10.1111/j.1369-1600.2008.00138.x. ISSN 1355-6215.
- ↑ Connors NJ, Hoffman RS (2013). "Experimental treatments for cocaine toxicity: a difficult transition to the bedside". J Pharmacol Exp Ther. 347 (2): 251–7. doi:10.1124/jpet.113.206383. PMID 23978563.
- ↑ Mittleman MA, Mintzer D, Maclure M, Tofler GH, Sherwood JB, Muller JE (1999). "Triggering of myocardial infarction by cocaine". Circulation. 99 (21): 2737–41. doi:10.1161/01.cir.99.21.2737. PMID 10351966.
- ↑ Maceira, Alicia M; Ripoll, Carmen; Cosin-Sales, Juan; Igual, Begoña; Gavilan, Mirella; Salazar, Jose; Belloch, Vicente; Pennell, Dudley J (2014). "Long term effects of cocaine on the heart assessed by cardiovascular magnetic resonance at 3T". Journal of Cardiovascular Magnetic Resonance. 16 (1): 26. doi:10.1186/1532-429X-16-26. ISSN 1532-429X.
- ↑ Richards, John R.; Garber, Dariush; Laurin, Erik G.; Albertson, Timothy E.; Derlet, Robert W.; Amsterdam, Ezra A.; Olson, Kent R.; Ramoska, Edward A.; Lange, Richard A. (2016). "Treatment of cocaine cardiovascular toxicity: a systematic review". Clinical Toxicology. 54 (5): 345–364. doi:10.3109/15563650.2016.1142090. ISSN 1556-3650.
- ↑ Anderson, Jeffrey L.; Adams, Cynthia D.; Antman, Elliott M.; Bridges, Charles R.; Califf, Robert M.; Casey, Donald E.; Chavey, William E.; Fesmire, Francis M.; Hochman, Judith S.; Levin, Thomas N.; Lincoff, A. Michael; Peterson, Eric D.; Theroux, Pierre; Wenger, Nanette K.; Wright, R. Scott; Zoghbi, William A.; Arend, Thomas E.; Oetgen, William J.; May, Charlene; Bradfield, Lisa; Keller, Sue; Ramadhan, Ezaldeen; Tomaselli, Gordon F.; Brown, Nancy; Robertson, Rose Marie; Whitman, Gayle R.; Bezanson, Judy L.; Hundley, Jody (2013). "2012 ACCF/AHA Focused Update Incorporated Into the ACCF/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction". Circulation. 127 (23). doi:10.1161/CIR.0b013e31828478ac. ISSN 0009-7322.
- ↑ Zun, Leslie S. (2018). "Evidence-Based Review of Pharmacotherapy for Acute Agitation. Part 1: Onset of Efficacy". The Journal of Emergency Medicine. 54 (3): 364–374. doi:10.1016/j.jemermed.2017.10.011. ISSN 0736-4679.
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|doi=value (help). Missing or empty|title=(help) - ↑ 14.0 14.1 Spiller, Henry A.; Hays, Hannah L.; Aleguas, Alfred (2013). "Overdose of Drugs for Attention-Deficit Hyperactivity Disorder: Clinical Presentation, Mechanisms of Toxicity, and Management". CNS Drugs. 27 (7): 531–543. doi:10.1007/s40263-013-0084-8. ISSN 1172-7047.
- ↑ Mathew, O P (2010). "Apnea of prematurity: pathogenesis and management strategies". Journal of Perinatology. 31 (5): 302–310. doi:10.1038/jp.2010.126. ISSN 0743-8346.
- ↑ Pesta, Dominik H; Angadi, Siddhartha S; Burtscher, Martin; Roberts, Christian K (2013). "The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance". Nutrition & Metabolism. 10 (1): 71. doi:10.1186/1743-7075-10-71. ISSN 1743-7075.
- ↑ van Dam, Rob M.; Campion, Edward W.; Hu, Frank B.; Willett, Walter C. (2020). "Coffee, Caffeine, and Health". New England Journal of Medicine. 383 (4): 369–378. doi:10.1056/NEJMra1816604. ISSN 0028-4793.
- ↑ Cappelletti, Simone; Daria, Piacentino; Sani, Gabriele; Aromatario, Mariarosaria (2015). "Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug?". Current Neuropharmacology. 13 (1): 71–88. doi:10.2174/1570159X13666141210215655. ISSN 1570-159X.