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Sunday, August 10, 2025

CNS stimulants


Overview
CNS stimulants are a diverse group of drugs that enhance brain and spinal cord activity by increasing neuronal excitation and neurotransmitter release or by inhibiting neurotransmitter reuptake. They are used clinically to treat conditions such as attention-deficit hyperactivity disorder (ADHD), narcolepsy, and certain cases of treatment-resistant depression, and are also found in some appetite suppressants. Many CNS stimulants have a high potential for misuse and dependence due to their effects on the brain’s reward pathways.

Mechanism of Action
CNS stimulants work via different but often overlapping mechanisms:

  • Catecholamine reuptake inhibition: Blocking dopamine (DA) and norepinephrine (NE) transporters, increasing synaptic levels (e.g., amphetamines, methylphenidate).

  • Increased neurotransmitter release: Promoting release of DA and NE from presynaptic vesicles (e.g., amphetamines).

  • Adenosine receptor antagonism: Reducing inhibitory neurotransmission and promoting wakefulness (e.g., caffeine).

  • Histamine, orexin, and dopamine modulation: Used in newer wake-promoting agents (e.g., modafinil, solriamfetol, pitolisant).

Major Classes and Examples

  1. Amphetamine Derivatives

    • Examples: Amphetamine sulfate, Dextroamphetamine, Lisdexamfetamine, Methamphetamine

    • Uses: ADHD, narcolepsy, sometimes off-label for depression in refractory cases

    • Mechanism: Promote DA and NE release, inhibit reuptake, inhibit monoamine oxidase at higher doses

  2. Methylphenidate and Analogues

    • Examples: Methylphenidate, Dexmethylphenidate

    • Uses: ADHD, narcolepsy

    • Mechanism: Primarily block DA and NE reuptake

  3. Wake-Promoting Agents

    • Examples: Modafinil, Armodafinil, Solriamfetol, Pitolisant

    • Uses: Narcolepsy, obstructive sleep apnea–related residual sleepiness, shift work disorder

    • Mechanism: Modulate DA reuptake, orexin, histamine, and other wakefulness pathways (exact mechanisms vary)

  4. Xanthine Derivatives

    • Examples: Caffeine, Theophylline, Theobromine

    • Uses: Apnea of prematurity (caffeine, theophylline), alertness, mild bronchodilation

    • Mechanism: Adenosine receptor antagonism, phosphodiesterase inhibition at high doses

  5. Anorectics (Appetite Suppressants)

    • Examples: Phentermine, Diethylpropion, Benzphetamine, Phendimetrazine

    • Uses: Short-term adjunct in obesity management

    • Mechanism: Sympathomimetic amines that increase NE/DA in CNS, reducing appetite

Therapeutic Uses

  • ADHD (first-line: methylphenidate, amphetamines)

  • Narcolepsy and hypersomnia disorders

  • Shift work sleep disorder

  • Residual sleepiness in obstructive sleep apnea

  • Short-term weight management (in select patients)

  • Apnea of prematurity (caffeine citrate)

Contraindications (vary by agent)

  • Known hypersensitivity to the drug or class

  • Symptomatic cardiovascular disease, severe hypertension

  • Hyperthyroidism

  • Glaucoma (especially narrow-angle)

  • History of drug misuse (caution, not absolute)

  • MAOI use within the past 14 days (risk of hypertensive crisis with sympathomimetics)

Precautions

  • Monitor blood pressure and heart rate regularly

  • Use caution in patients with psychiatric disorders (may exacerbate psychosis, anxiety, mania)

  • Screen for cardiac risk before starting high-potency stimulants

  • Risk of tolerance, dependence, and abuse with prolonged use of amphetamine-type stimulants

Adverse Effects

  • Common: Insomnia, decreased appetite, weight loss, dry mouth, increased heart rate, anxiety, headache

  • Cardiovascular: Hypertension, palpitations, arrhythmias (rare but serious)

  • Neuropsychiatric: Mood swings, agitation, hallucinations, mania in predisposed individuals

  • GI: Nausea, abdominal pain

  • Others: Tics (may be unmasked or worsened), potential growth suppression in children with prolonged high-dose use

Drug Interactions

  • MAOIs: Hypertensive crisis risk with sympathomimetic stimulants

  • Other sympathomimetics: Additive cardiovascular effects

  • Antihypertensives: Possible reduced efficacy

  • CYP inducers/inhibitors: Can alter plasma concentrations of certain agents (e.g., modafinil induces CYP3A4)

  • Acidifying/alkalinizing agents: Can affect urinary excretion rates of amphetamines




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