Central nervous system stimulants: Difference between revisions
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==Overview== | ==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.<ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> <ref name="Kaleta2020">{{cite journal|last1=Kaleta|first1=Erin|title=Central nervous system stimulants|year=2020|pages=227–238|doi=10.1016/B978-0-12-815846-3.00014-4}}</ref> | [[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]].<ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> <ref name="Kaleta2020">{{cite journal|last1=Kaleta|first1=Erin|title=Central nervous system stimulants|year=2020|pages=227–238|doi=10.1016/B978-0-12-815846-3.00014-4}}</ref> | ||
==Cocaine== | ==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.<ref name="Benowitz1993">{{cite journal|last1=Benowitz|first1=Neal L.|title=Clinical Pharmacology and Toxicology of Cocaine|journal=Pharmacology & Toxicology|volume=72|issue=1|year=1993|pages=3–12|issn=09019928|doi=10.1111/j.1600-0773.1993.tb01331.x}}</ref> | 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.<ref name="Benowitz1993">{{cite journal|last1=Benowitz|first1=Neal L.|title=Clinical Pharmacology and Toxicology of Cocaine|journal=Pharmacology & Toxicology|volume=72|issue=1|year=1993|pages=3–12|issn=09019928|doi=10.1111/j.1600-0773.1993.tb01331.x}}</ref> | ||
===Mechanism of Action=== | ===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. <ref name="Kaleta2020">{{cite journal|last1=Kaleta|first1=Erin|title=Central nervous system stimulants|year=2020|pages=227–238|doi=10.1016/B978-0-12-815846-3.00014-4}}</ref> <ref name={{cite book | last = Kerrigan | first = Sarah | title = Principles of forensic toxicology | publisher = Springer | location = Cham | year = 2020 | isbn = 978-3-030-42917-1 }}</ref> <ref name={{cite book | last = Burtis | first = Carl | title = Tietz Textbook of Clinical Chemistry and Molecular Diagnostics | publisher = Elsevier Health Sciences | location = London | year = 2012 | isbn = 9781455759422 }}</ref> <ref name="SofuogluSewell2009">{{cite journal|last1=Sofuoglu|first1=Mehmet|last2=Sewell|first2=R. Andrew|title=Norepinephrine and stimulant addiction|journal=Addiction Biology|volume=14|issue=2|year=2009|pages=119–129|issn=13556215|doi=10.1111/j.1369-1600.2008.00138.x}}</ref> | 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. <ref name="Kaleta2020">{{cite journal|last1=Kaleta|first1=Erin|title=Central nervous system stimulants|year=2020|pages=227–238|doi=10.1016/B978-0-12-815846-3.00014-4}}</ref> <ref name={{cite book | last = Kerrigan | first = Sarah | title = Principles of forensic toxicology | publisher = Springer | location = Cham | year = 2020 | isbn = 978-3-030-42917-1 }}</ref> <ref name={{cite book | last = Burtis | first = Carl | title = Tietz Textbook of Clinical Chemistry and Molecular Diagnostics | publisher = Elsevier Health Sciences | location = London | year = 2012 | isbn = 9781455759422 }}</ref> <ref name="SofuogluSewell2009">{{cite journal|last1=Sofuoglu|first1=Mehmet|last2=Sewell|first2=R. Andrew|title=Norepinephrine and stimulant addiction|journal=Addiction Biology|volume=14|issue=2|year=2009|pages=119–129|issn=13556215|doi=10.1111/j.1369-1600.2008.00138.x}}</ref> | ||
===Acute Toxicity=== | ===Acute Toxicity=== | ||
Acute cocaine toxicity is characterized by sympathetic symptoms such as hypertension, hyperthermia, agitation, and seizures.<ref name="pmid23978563">{{cite journal| author=Connors NJ, Hoffman RS| title=Experimental treatments for cocaine toxicity: a difficult transition to the bedside. | journal=J Pharmacol Exp Ther | year= 2013 | volume= 347 | issue= 2 | pages= 251-7 | pmid=23978563 | doi=10.1124/jpet.113.206383 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23978563 }} </ref> 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.<ref name="pmid10351966">{{cite journal| author=Mittleman MA, Mintzer D, Maclure M, Tofler GH, Sherwood JB, Muller JE| title=Triggering of myocardial infarction by cocaine. | journal=Circulation | year= 1999 | volume= 99 | issue= 21 | pages= 2737-41 | pmid=10351966 | doi=10.1161/01.cir.99.21.2737 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10351966 }} </ref> 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.<ref name="MaceiraRipoll2014">{{cite journal|last1=Maceira|first1=Alicia M|last2=Ripoll|first2=Carmen|last3=Cosin-Sales|first3=Juan|last4=Igual|first4=Begoña|last5=Gavilan|first5=Mirella|last6=Salazar|first6=Jose|last7=Belloch|first7=Vicente|last8=Pennell|first8=Dudley J|title=Long term effects of cocaine on the heart assessed by cardiovascular magnetic resonance at 3T|journal=Journal of Cardiovascular Magnetic Resonance|volume=16|issue=1|year=2014|pages=26|issn=1532-429X|doi=10.1186/1532-429X-16-26}}</ref> | Acute cocaine [[toxicity]] is characterized by [[sympathetic symptoms]] such as [[hypertension]], [[hyperthermia]], agitation, and [[seizures]].<ref name="pmid23978563">{{cite journal| author=Connors NJ, Hoffman RS| title=Experimental treatments for cocaine toxicity: a difficult transition to the bedside. | journal=J Pharmacol Exp Ther | year= 2013 | volume= 347 | issue= 2 | pages= 251-7 | pmid=23978563 | doi=10.1124/jpet.113.206383 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23978563 }} </ref> 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.<ref name="pmid10351966">{{cite journal| author=Mittleman MA, Mintzer D, Maclure M, Tofler GH, Sherwood JB, Muller JE| title=Triggering of myocardial infarction by cocaine. | journal=Circulation | year= 1999 | volume= 99 | issue= 21 | pages= 2737-41 | pmid=10351966 | doi=10.1161/01.cir.99.21.2737 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10351966 }} </ref> 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]].<ref name="MaceiraRipoll2014">{{cite journal|last1=Maceira|first1=Alicia M|last2=Ripoll|first2=Carmen|last3=Cosin-Sales|first3=Juan|last4=Igual|first4=Begoña|last5=Gavilan|first5=Mirella|last6=Salazar|first6=Jose|last7=Belloch|first7=Vicente|last8=Pennell|first8=Dudley J|title=Long term effects of cocaine on the heart assessed by cardiovascular magnetic resonance at 3T|journal=Journal of Cardiovascular Magnetic Resonance|volume=16|issue=1|year=2014|pages=26|issn=1532-429X|doi=10.1186/1532-429X-16-26}}</ref> | ||
===Management=== | ===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.<ref name="RichardsGarber2016">{{cite journal|last1=Richards|first1=John R.|last2=Garber|first2=Dariush|last3=Laurin|first3=Erik G.|last4=Albertson|first4=Timothy E.|last5=Derlet|first5=Robert W.|last6=Amsterdam|first6=Ezra A.|last7=Olson|first7=Kent R.|last8=Ramoska|first8=Edward A.|last9=Lange|first9=Richard A.|title=Treatment of cocaine cardiovascular toxicity: a systematic review|journal=Clinical Toxicology|volume=54|issue=5|year=2016|pages=345–364|issn=1556-3650|doi=10.3109/15563650.2016.1142090}}</ref> | [[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.<ref name="RichardsGarber2016">{{cite journal|last1=Richards|first1=John R.|last2=Garber|first2=Dariush|last3=Laurin|first3=Erik G.|last4=Albertson|first4=Timothy E.|last5=Derlet|first5=Robert W.|last6=Amsterdam|first6=Ezra A.|last7=Olson|first7=Kent R.|last8=Ramoska|first8=Edward A.|last9=Lange|first9=Richard A.|title=Treatment of cocaine cardiovascular toxicity: a systematic review|journal=Clinical Toxicology|volume=54|issue=5|year=2016|pages=345–364|issn=1556-3650|doi=10.3109/15563650.2016.1142090}}</ref> | ||
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 | [[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.<ref name="AndersonAdams2013">{{cite journal|last1=Anderson|first1=Jeffrey L.|last2=Adams|first2=Cynthia D.|last3=Antman|first3=Elliott M.|last4=Bridges|first4=Charles R.|last5=Califf|first5=Robert M.|last6=Casey|first6=Donald E.|last7=Chavey|first7=William E.|last8=Fesmire|first8=Francis M.|last9=Hochman|first9=Judith S.|last10=Levin|first10=Thomas N.|last11=Lincoff|first11=A. Michael|last12=Peterson|first12=Eric D.|last13=Theroux|first13=Pierre|last14=Wenger|first14=Nanette K.|last15=Wright|first15=R. Scott|last16=Zoghbi|first16=William A.|last17=Arend|first17=Thomas E.|last18=Oetgen|first18=William J.|last19=May|first19=Charlene|last20=Bradfield|first20=Lisa|last21=Keller|first21=Sue|last22=Ramadhan|first22=Ezaldeen|last23=Tomaselli|first23=Gordon F.|last24=Brown|first24=Nancy|last25=Robertson|first25=Rose Marie|last26=Whitman|first26=Gayle R.|last27=Bezanson|first27=Judy L.|last28=Hundley|first28=Jody|title=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|journal=Circulation|volume=127|issue=23|year=2013|issn=0009-7322|doi=10.1161/CIR.0b013e31828478ac}}</ref> | ||
Antipsychotics control agitation and psychosis, and combination treatment with benzodiazepines and antipsychotics are more effective than monotherapy.<ref name="Zun2018">{{cite journal|last1=Zun|first1=Leslie S.|title=Evidence-Based Review of Pharmacotherapy for Acute Agitation. Part 1: Onset of Efficacy|journal=The Journal of Emergency Medicine|volume=54|issue=3|year=2018|pages=364–374|issn=07364679|doi=10.1016/j.jemermed.2017.10.011}}</ref> | [[Antipsychotics]] control [[agitation]] and [[psychosis]], and combination treatment with [[benzodiazepines]] and [[antipsychotics]] are more effective than monotherapy.<ref name="Zun2018">{{cite journal|last1=Zun|first1=Leslie S.|title=Evidence-Based Review of Pharmacotherapy for Acute Agitation. Part 1: Onset of Efficacy|journal=The Journal of Emergency Medicine|volume=54|issue=3|year=2018|pages=364–374|issn=07364679|doi=10.1016/j.jemermed.2017.10.011}}</ref> | ||
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.<ref name="Kaleta2020">{{cite journal|last1=Kaleta|first1=Erin|title=Central nervous system stimulants|year=2020|pages=227–238|doi=10.1016/B978-0-12-815846-3.00014-4}}</ref> | [[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]].<ref name="Kaleta2020">{{cite journal|last1=Kaleta|first1=Erin|title=Central nervous system stimulants|year=2020|pages=227–238|doi=10.1016/B978-0-12-815846-3.00014-4}}</ref> | ||
==Amphetamines== | ==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.<ref name="Kaleta2020">{{cite journal|last1=Kaleta|first1=Erin|title=Central nervous system stimulants|year=2020|pages=227–238|doi=10.1016/B978-0-12-815846-3.00014-4}}</ref> Clinically, amphetamine is a recognized drug in the treatment of Attention Deficit Hyperactivity Disorder (ADHD), depression, and narcolepsy.<ref>{{cite journal|doi=10.1177/0269881113482532 jop.sagepub.com}}</ref> | 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.<ref name="Kaleta2020">{{cite journal|last1=Kaleta|first1=Erin|title=Central nervous system stimulants|year=2020|pages=227–238|doi=10.1016/B978-0-12-815846-3.00014-4}}</ref> Clinically, amphetamine is a recognized drug in the treatment of Attention Deficit Hyperactivity Disorder (ADHD), depression, and narcolepsy.<ref>{{cite journal|doi=10.1177/0269881113482532 jop.sagepub.com}}</ref> | ||
===Mechanism of Action=== | ===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. <ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> 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.<ref name="Kaleta2020">{{cite journal|last1=Kaleta|first1=Erin|title=Central nervous system stimulants|year=2020|pages=227–238|doi=10.1016/B978-0-12-815846-3.00014-4}}</ref> <ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> <ref>{{cite journal|doi=10.1177/0269881113482532 jop.sagepub.com}}</ref> | 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]]. <ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> 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]].<ref name="Kaleta2020">{{cite journal|last1=Kaleta|first1=Erin|title=Central nervous system stimulants|year=2020|pages=227–238|doi=10.1016/B978-0-12-815846-3.00014-4}}</ref> <ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> <ref>{{cite journal|doi=10.1177/0269881113482532 jop.sagepub.com}}</ref> | ||
===Adverse Effects=== | ===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.<ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> <ref>{{cite journal|doi=10.1177/0269881113482532 jop.sagepub.com}}</ref> | 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.<ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> <ref>{{cite journal|doi=10.1177/0269881113482532 jop.sagepub.com}}</ref> | ||
===Acute Toxicity=== | ===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 | [[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]].<ref name="SpillerHays2013">{{cite journal|last1=Spiller|first1=Henry A.|last2=Hays|first2=Hannah L.|last3=Aleguas|first3=Alfred|title=Overdose of Drugs for Attention-Deficit Hyperactivity Disorder: Clinical Presentation, Mechanisms of Toxicity, and Management|journal=CNS Drugs|volume=27|issue=7|year=2013|pages=531–543|issn=1172-7047|doi=10.1007/s40263-013-0084-8}}</ref> | ||
===Management=== | ===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. | 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. | 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. | [[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. | [[Sinus tachycardia]], the most common [[ECG]] abnormality in these patients, usually does not require any intervention. [[Hypertension]] and [[tachycardia]] usually respond to [[benzodiazepines]]. | ||
<ref name="SpillerHays2013">{{cite journal|last1=Spiller|first1=Henry A.|last2=Hays|first2=Hannah L.|last3=Aleguas|first3=Alfred|title=Overdose of Drugs for Attention-Deficit Hyperactivity Disorder: Clinical Presentation, Mechanisms of Toxicity, and Management|journal=CNS Drugs|volume=27|issue=7|year=2013|pages=531–543|issn=1172-7047|doi=10.1007/s40263-013-0084-8}}</ref> | <ref name="SpillerHays2013">{{cite journal|last1=Spiller|first1=Henry A.|last2=Hays|first2=Hannah L.|last3=Aleguas|first3=Alfred|title=Overdose of Drugs for Attention-Deficit Hyperactivity Disorder: Clinical Presentation, Mechanisms of Toxicity, and Management|journal=CNS Drugs|volume=27|issue=7|year=2013|pages=531–543|issn=1172-7047|doi=10.1007/s40263-013-0084-8}}</ref> | ||
==Caffeine== | ==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.<ref name="Mathew2010">{{cite journal|last1=Mathew|first1=O P|title=Apnea of prematurity: pathogenesis and management strategies|journal=Journal of Perinatology|volume=31|issue=5|year=2010|pages=302–310|issn=0743-8346|doi=10.1038/jp.2010.126}}</ref> <ref name="PestaAngadi2013">{{cite journal|last1=Pesta|first1=Dominik H|last2=Angadi|first2=Siddhartha S|last3=Burtscher|first3=Martin|last4=Roberts|first4=Christian K|title=The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance|journal=Nutrition & Metabolism|volume=10|issue=1|year=2013|pages=71|issn=1743-7075|doi=10.1186/1743-7075-10-71}}</ref> 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.<ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> | [[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.<ref name="Mathew2010">{{cite journal|last1=Mathew|first1=O P|title=Apnea of prematurity: pathogenesis and management strategies|journal=Journal of Perinatology|volume=31|issue=5|year=2010|pages=302–310|issn=0743-8346|doi=10.1038/jp.2010.126}}</ref> <ref name="PestaAngadi2013">{{cite journal|last1=Pesta|first1=Dominik H|last2=Angadi|first2=Siddhartha S|last3=Burtscher|first3=Martin|last4=Roberts|first4=Christian K|title=The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance|journal=Nutrition & Metabolism|volume=10|issue=1|year=2013|pages=71|issn=1743-7075|doi=10.1186/1743-7075-10-71}}</ref> 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.<ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> | ||
===Mechanism of Action=== | ===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.<ref name="van DamCampion2020">{{cite journal|last1=van Dam|first1=Rob M.|last2=Campion|first2=Edward W.|last3=Hu|first3=Frank B.|last4=Willett|first4=Walter C.|title=Coffee, Caffeine, and Health|journal=New England Journal of Medicine|volume=383|issue=4|year=2020|pages=369–378|issn=0028-4793|doi=10.1056/NEJMra1816604}}</ref> | 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.<ref name="van DamCampion2020">{{cite journal|last1=van Dam|first1=Rob M.|last2=Campion|first2=Edward W.|last3=Hu|first3=Frank B.|last4=Willett|first4=Walter C.|title=Coffee, Caffeine, and Health|journal=New England Journal of Medicine|volume=383|issue=4|year=2020|pages=369–378|issn=0028-4793|doi=10.1056/NEJMra1816604}}</ref> | ||
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. | 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.<ref name="CappellettiDaria2015">{{cite journal|last1=Cappelletti|first1=Simone|last2=Daria|first2=Piacentino|last3=Sani|first3=Gabriele|last4=Aromatario|first4=Mariarosaria|title=Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug?|journal=Current Neuropharmacology|volume=13|issue=1|year=2015|pages=71–88|issn=1570159X|doi=10.2174/1570159X13666141210215655}}</ref> | Lastly, it competitively inhibits [[phosphodiesterase]], which inhibits cyclic adenosine monophosphate degradation [[(cAMP)]]. However, this mechanism requires high doses of caffeine.<ref name="CappellettiDaria2015">{{cite journal|last1=Cappelletti|first1=Simone|last2=Daria|first2=Piacentino|last3=Sani|first3=Gabriele|last4=Aromatario|first4=Mariarosaria|title=Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug?|journal=Current Neuropharmacology|volume=13|issue=1|year=2015|pages=71–88|issn=1570159X|doi=10.2174/1570159X13666141210215655}}</ref> | ||
===Toxicity=== | ===Toxicity=== | ||
High levels of caffeine (1.2 g or higher) induce anxiety, restlessness, nervousness, insomnia, and agitation.<ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> | High levels of caffeine (1.2 g or higher) induce anxiety, restlessness, nervousness, insomnia, and agitation.<ref name="George2000">{{cite journal|last1=George|first1=Alan J.|title=Central nervous system stimulants|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=14|issue=1|year=2000|pages=79–88|issn=1521690X|doi=10.1053/beem.2000.0055}}</ref> | ||
== | ==Modafinil== | ||
Modafinil (2-[(diphenylmethyl) sulfinyl] 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.{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK531476/ |title=Modafinil - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}} | |||
===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. <ref name="HashemianFarhadi2020">{{cite journal|last1=Hashemian|first1=Seyed MohammadReza|last2=Farhadi|first2=Tayebeh|title=A review on modafinil: the characteristics, function, and use in critical care|journal=Journal of Drug Assessment|volume=9|issue=1|year=2020|pages=82–86|issn=2155-6660|doi=10.1080/21556660.2020.1745209}}</ref> | |||
===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.{{cite web |url=https://www.webmd.com/drugs/2/drug-16962/modafinil-oral/details |title=Modafinil Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD |format= |work= |accessdate=}} | |||
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The | |||
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= | |||
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==References== | ==References== | ||
Latest revision as of 18:46, 6 July 2021
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(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.[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(MAO) 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, 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]
Modafinil
Modafinil (2-[(diphenylmethyl) sulfinyl] 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".
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. [19]
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".
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.
- ↑ . doi:10.1177/0269881113482532 jop.sagepub.com Check
|doi=value (help). Missing or empty|title=(help) - ↑ . doi:10.1177/0269881113482532 jop.sagepub.com Check
|doi=value (help). Missing or empty|title=(help) - ↑ . doi:10.1177/0269881113482532 jop.sagepub.com Check
|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.
- ↑ Hashemian, Seyed MohammadReza; Farhadi, Tayebeh (2020). "A review on modafinil: the characteristics, function, and use in critical care". Journal of Drug Assessment. 9 (1): 82–86. doi:10.1080/21556660.2020.1745209. ISSN 2155-6660.