Stimulants

Mechanism of Action

The general mechanism of stimulants revolves around increased catecholamine levels and increased agonistic activity at adrenergic receptors. 

Caffeine

• Caffeine has a unique mechanism as a stimulant as it works as an inhibitor at the adenosine receptors. Agonism at these receptors induces a sensation of drowsiness, and therefore inhibition at these receptors leads to increased energy levels. 
• Caffeine also increases intraocular pressure in those affected with glaucoma.[3]

Amphetamines

• The general mechanism of action of amphetamines is the induction of catecholamines, specifically norepinephrine and dopamine. These catecholamines lead to increased energy levels, euphoria, increased libido, and higher cognition.[4] This class also includes non-therapeutic agents such as 3,4-methylenedioxymethamphetamine (MDMA, aka ecstasy), methylenedioxypyrovalerone (MDPV), and mephedrone.[5][6][7][5]

Methylphenidate

• This drug blocks the dopamine transporter (DAT) and the norepinephrine transporter (NET), leading to increased dopamine and norepinephrine levels with the inhibition of their reuptake.[8] 

Ephedrine

• The primary mechanism of ephedrine is increased norepinephrine activity at the adrenergic receptors. Pseudoephedrine specifically works also as a nasal and sinus decongestant.[9] 

Cocaine

• The induction of most of the effects of cocaine is through the blockade of the dopamine transporter protein. This results in increased dopamine levels at the synaptic cleft, and hence the effects of dopamine become amplified. 

Pseudoephedrine

• Pseudoephedrine is a drug used as a nasal decongestant and stimulant.[10] It is a sympathomimetic agent that belongs to the amphetamine and phenethylamine drug classes. It appears in a number of over-the-counter formulations, including combinations with guaifenesin, antihistamines, acetaminophen, and dextromethorphan.

Khat (Catha edulis)

• Khat is a flowering plant indigenous to the Arabian Peninsula and the Horn of Africa.[11] It contains a substance called cathinone, and the World Health Organization considers it a potential drug of abuse, although they do not rate it as a serious addiction risk. It is a keto-amphetamine and is banned in the USA.

Modafinil

• This is a CNS-stimulating agent used to treat sleepiness related to obstructive sleep apnea, narcolepsy, and shift-worker disorder. It is a weak dopamine uptake inhibitor, although the precise mechanism for its stimulating effects remains unknown.

Additional stimulants are available, especially in pre-workout supplements, which have direct agonistic effects on adrenergic receptors. Examples include synephrine, which is present in many supplements, and methylsynephrine, which the WADA banned. Other known stimulants, such as 1,3-dimethlamylamine (DMAA), have lesser-known pharmacologic mechanisms.[12][13]

Administration

The primary method of administration for stimulants is oral intake. Recreational administration of stimulants also occurs by intramuscular and/or intravascular injection, smoking, and intranasal administration; this will vary by individual agent.

Adverse Effects

Stimulants can induce a broad range of short-term and long-term adverse effects. The side effect profile is dependent on numerous variables. The major factors that influence adverse effect outcomes are the user's body weight, the specific stimulant used, the dose of the agent taken, and tolerance. Other factors include the use of other drugs and stimulants and oral intake on an empty stomach. The adverse effects of stimulants include the following[14][15][16]:

• Decreased appetite - possible therapeutic effect in specific users
• Anxiety
• Jitteriness
• Headaches
• Weight loss
• Insomnia
• Psychosis
• Pruritus
• Paranoia
• Sweating
• Palpitations
• Shortness of breath
• Chest pain
• Hypertension
• Tachycardia
• Seizures
• Arrhythmias
• EKG abnormalities: inappropriate sinus tachycardia, sinus arrhythmia, prolonged QT, premature ventricular contractions, ventricular tachycardia
• Cerebrovascular event
• Sudden cardiac death

The above list is general and depends on a number of factors, including the specific agent, mode of administration, and the underlying health and comorbidities of the person using the drug.[14][15][16]

If intranasal administration occurs, particularly with cocaine, there is a risk of nose bleeds and significant rhinorrhea. 

Other long-term adverse effects from stimulant use involve increased risks of strokes and myocardial infarctions. The reasoning behind the elevated risks appears to be multifactorial and primarily due to the cardiovascular effects of stimulants.

Contraindications

There are numerous relative contraindications to the use of stimulants. Patients with advanced arteriosclerosis should use minimal stimulants given the elevated risk of myocardial infarction, as stimulants elevate cardiac demand. Also, patients with severe hypertension will exacerbate their existing elevated high blood pressure when using stimulants and, therefore, should minimize their use. Untreated hyperthyroidism, glaucoma, and a recent stroke are also relative contraindications to stimulant use. Cardiac arrhythmias are also known to worsen and even result from certain stimulants; therefore, individuals so affected should avoid stimulant use.[17]

Younger patients under the age of 12 and pregnant patients should avoid using stimulants. From a general perspective, some patients are susceptible to stimulants and should either avoid using or minimize their dose.

Monitoring

It is prudent for the clinician considering stimulant therapy for any condition for which it is indicated to perform a careful assessment of the patient by using a targeted cardiac history (eg, patient history of previously detected cardiac disease, palpitations, syncope, or seizures; a family history of sudden death in children or young adults; hypertrophic cardiomyopathy; long QT syndrome) and a physical examination, including a careful cardiac examination. This approach is appropriate for adults and children.[18][19]

Toxicity

Treatment of a stimulant overdose depends on the specific agent used, the ongoing adverse effects, and the potential risk for further adverse effects. The generally available options for treating stimulant toxicity are benzodiazepines, beta-blockers, antiarrhythmic agents, and antihypertensive medications. Certain medications under these classes of drugs may be contraindicated depending on the specific drug used. Benzodiazepines lower the associated anxiety of stimulant toxicity and may improve the patient's vital signs. They are also the primary option if the patient is experiencing seizures. Beta-blockers are useful for lowering the patient's heart rate, given that tachycardia is a very common symptom of stimulant overdose. As well, they can improve the patient's hypertensive state. Antiarrhythmic medications are generally reserved for ventricular arrhythmias that result from stimulant toxicity.[20]

It is critical to confirm the specific drug that induces the stimulant toxicity given the potential treatment contraindications. For example, cocaine overdoses are a frequent cause of stimulant toxicity. While they induce tachycardia, chest pain, and hypertension, the use of beta-blockers may potentially be cardiotoxic to a patient who has overdosed on cocaine.[21]

Enhancing Healthcare Team Outcomes

Stimulants make up a broad range of drugs; many find a use for recreational and performance enhancement reasons. Primary care clinicians (including MDs, DOs, NPOs, and PAs) can significantly improve healthcare outcomes by educating their patients on the short-term and long-term effects of stimulant use. While caffeine is a relatively safe stimulant, other stimulants used by athletes, students, and recreational users can pose a significant health threat. It is essential not to overlook them in the patient's social history gathering process. Furthermore, pharmacists are readily accessible by patients and hence can carry out a critical role in educating the public; this is especially true on pre-workout supplements containing various stimulants. When a patient is prescribed a stimulant, the pharmacist can verify that no drug-drug interactions exist that can lead to an adverse event. This again emphasizes the point already made about collecting an accurate patient social and medication/supplement history.

Monitoring patient stimulant usage is not confined to illicit, recreational, or non-prescribed use of these agents. When prescribing stimulant medications for legitimate purposes (ADHD, narcolepsy, etc.), the onus remains on the entire interprofessional team to monitor the patient's progress and condition and openly share information among all interprofessional team members. All healthcare team members, including clinicians, nurses, and pharmacists, must coordinate their activities and exercise open communication to help patients not misuse stimulant drugs. [Level 5]