Psychostimulants | Amphetamines

Amphetamines

Amphetamine is phenylisopropylamine.

Alterations of the three main parts of the phenylisopropylamine backbone ultimately determines its pharmacological effects

  • Amine Group: Most common alteration is at the amine group, which is thought to alter the stimulant like properties of amphetamines
  • Isopropyl Group: Needed to maintain potency
  • Phenyl Group: Changes are associated with decrease in amphetamine properties (methoxy alterations are associated with hallucinogenic properties)

Stereospecificity (D,L – stereoisomers)

  • Amphetamine mixed salts are typically a mixture of dextroamphetamine (D-amphetamine) and levoamphetamine (L-amphetamine). 
  • D-amphetamine is almost twice as potent as the levo form in promoting wakefulness
  • D and L are of equal potency in reducing cataplexy and REM sleep
  • Stereospecificity also determines the degree of dopamine reuptake inhibition (in rat models)
  • D-amphetamine is four times more potent than the L-isomer in promoting lever pressing in rats (model of reinforcement)

Mechanism of Action

  • Amphetamine rapidly diffuses directly into neuron terminals and enters neuronal vesicles which causes release of dopamine and norepinephrine
  • Amphetamine also inhibits reuptake of these catecholamines by inhibition of the their respective reuptake transporters

Pharmacokinetics

  • Amphetamine is lipid soluble, distributes rapidly into tissues, and readily crosses the blood brain barrier.
  • Amphetamine reaches peak levels in ~2 hours
  • Half life of amphetamine is approximately 16-30 hours.
  • 30% of amphetamine is excreted unchanged

Side Effects

  • Nervousness
  • Agitation
  • Decreased sleep
  • Diaphoresis (sweating)
  • Anorexia
  • Psychosis (rare with oral formulations) 

Methamphetamine

  • Methamphetamine is more potent but also more toxic than amphetamine
  • Methamphetamine can cause destruction of dopaminergic neurons in the basal ganglia (increased likelihood of future parkinsonism?)
  • Psychosis, rhabdomyolysis, convulsions, arrhythmia, hyperpyrexia, and death may result from inhaled or injected methamphetamine
  • MDMA “Ecstasy” is toxic to both serotonergic and dopaminergic neurons

 

 

ADDERALL (IR,XR*)

(D,L) Amphetamine

*IR (Instant Release) | XR (Extended Release)

HALF-LIFE: 9-14 hours

TIME TO EFFECT: IR ~1 hour | XR ~1-2 hours

PEAK IN PLASMA: IR 3 hours | XR 7 hours

DURATION OF CLINICAL ACTION: IR 6-9 hours | XR 6-10 hours

PROTEIN BINDING: ~20%

METABOLISM: CYP2D6 (partially)

WITH/WITHOUT FOOD (PO): Taking with food may delay peak actions. pH of food alters absorption and elimination of amphetamines. GI and urinary Acidifying agents decrease plasma levels of amphetamines. GI and urinary alkalinizing agents increase plasma levels of amphetamines. 

STARTING DOSE: 5mg-10mg

TARGET DOSING RANGE: 10mg-60mg per day

BEST TIME TO DOSE: Morning (but depends on formulation)

HOW TO DOSE:

  • IR: Initial 5mg twice daily. Increase dose by 5mg-10mg per day each week based on response and tolerability. Typically dose every 4-6 hours. Maximum daily dose generally 40mg-60mg. Some patients may require higher dosages.
  • XR: Initial 10mg every morning. Increase dose by 5mg-10mg at weekly intervals based on response and tolerability. Maximum daily dose generally 30mg-60mg. Some patients may require higher dosages.

NOTABLE INTERACTIONS:

  • GI/Urinary Acidifying agents decrease plasma levels of amphetamine
  • GI/Urinary Alkalinizing agents increase plasma levels of amphetamine
  • Desipramine should be used with extreme caution if used with amphetamine
  • Dopamine antagonists such as haloperidol and chlorpromazine as well as lithium may inhibit stimulant effects of amphetamines
  • Amphetamines increase the analgesic effects of meperidine
  • Avoid using with monoamine oxidase inhibitors due to risk of hypertensive crises and malignant hyperthermia

NOTABLE SIDE EFFECTS:

  • Insomnia
  • Headache
  • Anxiety
  • Tremor
  • Anorexia
  • Dry Mouth
  • Weight loss
  • Seizures (rarely with PO)
  • Psychosis (rarely with PO)
  • Elevated Blood Pressure
  • Tachycardia
  • Sudden death has been reported in patients with preexisting cardiac structural abnormalities

PREGNANCY: Avoid if possible (discuss with a medical professional)

BREASTFEEDING: Avoid if possible (discuss with a medical professional)

FDA INDICATIONS:
1) Attention Deficit Hyperactivity Disorder in children and adults

2) Narcolepsy

3) Exogenous obesity

ADDITIONAL INFORMATION

  • Ratio of D:L Amphetamine is 3:1

DEXEDRINE (IR,ER*)

(D) Amphetamine

*IR (Instant Release) | ER (Extended Release)

HALF-LIFE: 10-12 hours

TIME TO EFFECT: IR ~1 hour | ER ~1-2 hours

PEAK IN PLASMA: IR 3 hours | ER 7 hours

DURATION OF CLINICAL ACTION: IR 3-9 hours | ER 6-10 hours

PROTEIN BINDING: ~20%

METABOLISM: CYP2D6 (partially)

WITH/WITHOUT FOOD (PO): Taking with food may delay peak actions. pH of food alters absorption and elimination of amphetamines. GI and urinary Acidifying agents decrease plasma levels of amphetamines. GI and urinary alkalinizing agents increase plasma levels of amphetamines. 

STARTING DOSE: 5mg-10mg

TARGET DOSING RANGE: 5mg-40mg per day

BEST TIME TO DOSE: Morning (but depends on formulation)

HOW TO DOSE:

  • IR: Initial 5mg twice daily. Increase dose by 5mg-10mg per day each week based on response and tolerability. Typically dose every 4-6 hours. Maximum daily dose generally 40mg-60mg. Some patients may require higher dosages.
  • ER: Initial 5mg-10mg every morning. Increase dose by 5mg-10mg at weekly intervals based on response and tolerability. Maximum daily dose generally 20mg-40mg. Some patients may require higher dosages.

NOTABLE INTERACTIONS:

  • GI/Urinary Acidifying agents decrease plasma levels of amphetamine
  • GI/Urinary Alkalinizing agents increase plasma levels of amphetamine
  • Desipramine should be used with extreme caution if used with amphetamine
  • Dopamine antagonists such as haloperidol and chlorpromazine as well as lithium may inhibit stimulant effects of amphetamines
  • Amphetamines increase the analgesic effects of meperidine
  • Avoid using with monoamine oxidase inhibitors due to risk of hypertensive crises and malignant hyperthermia

NOTABLE SIDE EFFECTS:

  • Insomnia
  • Headache
  • Anxiety
  • Tremor
  • Anorexia
  • Dry Mouth
  • Weight loss
  • Seizures (rarely with PO)
  • Psychosis (rarely with PO)
  • Elevated Blood Pressure
  • Tachycardia
  • Sudden death has been reported in patients with preexisting cardiac structural abnormalities

PREGNANCY: Avoid if possible (discuss with a medical professional)

BREASTFEEDING: Avoid if possible (discuss with a medical professional)

FDA INDICATIONS:
1) Attention Deficit Hyperactivity Disorder in children and adults

2) Narcolepsy

ADDITIONAL INFORMATION

  • Dextroamphetamine only
  • Anecdotally, patients experience less peripheral sympathetic side effects and anxiety with D-Amphetamine compared to D,L-Amphetamine

VYVANSE

Lisdexamfetamine

HALF-LIFE: lisdexamfetamine (prodrug): <1 hour | dextroamphetamine (active metabolite): 10-13 hours (dextroamphetamine)

TIME TO EFFECT: Variable. But generally longer than other amphetamine formulations

DURATION OF CLINICAL ACTION: Variable

METABOLISM: Minimal CYP450 involvement

WITH/WITHOUT FOOD (PO): Food does not affect absorption of lisdexamfetamine, but like other amphetamines, acidification of the urine or GI tract results in more rapid clearance. 

STARTING DOSE: 20mg-30mg

TARGET DOSING RANGE: 20mg-70mg per day

BEST TIME TO DOSE: Morning 

HOW TO DOSE:

  • Initial 20mg-30mg every morning. Increase dose by 10mg-20mg at weekly intervals based on response and tolerability. Maximum daily dose generally 70mg. Some patients may require higher dosages.

NOTABLE INTERACTIONS:

  • GI/Urinary Acidifying agents decrease plasma levels of amphetamine
  • GI/Urinary Alkalinizing agents increase plasma levels of amphetamine
  • Desipramine should be used with extreme caution if used with amphetamine
  • Dopamine antagonists such as haloperidol and chlorpromazine as well as lithium may inhibit stimulant effects of amphetamines
  • Amphetamines increase the analgesic effects of meperidine
  • Avoid using with monoamine oxidase inhibitors due to risk of hypertensive crises and malignant hyperthermia

NOTABLE SIDE EFFECTS:

  • Insomnia
  • Headache
  • Anxiety
  • Tremor
  • Anorexia
  • Dry Mouth
  • Weight loss
  • Seizures (rarely with PO)
  • Psychosis (rarely with PO)
  • Elevated Blood Pressure
  • Tachycardia
  • Sudden death has been reported in patients with preexisting cardiac structural abnormalities

PREGNANCY: Avoid if possible (discuss with a medical professional)

BREASTFEEDING: Avoid if possible (discuss with a medical professional)

FDA INDICATIONS:
1) Attention Deficit Hyperactivity Disorder in children and adults

2) Binge Eating Disorder

ADDITIONAL INFORMATION

  • Lisdexamfetamine (inactive prodrug) is dextroamphetamine with lysine attached to it. 
  • Lisdexamfetamine is metabolized primarily by gastrointestinal enzymes to the active metabolite dextroamphetamine.
  • Snorting or injecting lisdexamfetamine will result in “highs” and therefore less abuse potential
  • Anecdotally, patients experience less peripheral sympathetic side effects and anxiety with lisdexamfetamine (likely related to slower onset/offset of action but may also be due to stereospecificity of dextroamphetamine (active metabolite). 
  • Lisdexamfetamine 70mg is approximately equivalent to 30mg of D,L-Amphetamine (Adderall)
  • Some evidence suggests lisdexamfetamine may be beneficial for residual depressive symptoms (but controversial as RCTs failed to show separation from placebo in treatment resistant depression)

REFERENCES:

  1. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  2. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  3. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
  4. Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
  5. Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
  6. Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.
  7. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.
  8. Hales et al. The American Psychiatric Association Publishing Textbook of Psychiatry. 6th Ed.
  9. Goldberg & Ernst. Managing Side Effects of Psychotropic Medications. 1st Ed. 2012. APP.
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