Dexamphetamine and Lisdexamfetamine- Mechanism of Action, Side Effects and Dosing

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Amphetamine (AMPH):

Amphetamine has a d-isomer and an l-isomer.

The d-isomer is the active isomer.

Mechanism of action

Amphetamine has the following mechanisms:

  1. Competitive inhibitor at DAT competing with dopamine and noradrenaline at NAT.
  2. Competitive inhibitor of VMAT

3. High levels amphetamine will lead to the displacement of dopamine from the vesicle into the terminal

4. Reversal of DAT.

 

5. Action on NAT: Reuptake inhibitor of Noradrenaline increasing extracellular levels of Noradrenaline. [Kuczenski et al, 1995]

 

6. Action of SERT and Serotonin (5-HT)

Amphetamines block SERT and can also release 5-HT presynaptically via a carrier-mediated process leading to increase in extracellular serotonin.

Note: Methylphenidate on the other hand does not increase extracellular 5-HT. [Feinberg, 2004]

7. Low doses of amphetamine may act mainly as blockers at the neuronal transporter. However, as the dose is increased, the AMPH derivatives can accumulate in the cytoplasm to sufficiently high concentrations to disrupt vesicular storage, thus facilitating transmitter release from all three biogenic amine nerve terminals. [Kuczenski et al, 1995]

 

Metabolism:

All types of AMPH are metabolised in the liver by side-chain oxidative deamination and by ring hydroxylation. Since acidification of the urine increases the urinary output of AMPH.

Therefore, taking medicine with ascorbic acid or fruit juice may decrease its absorption, while the use of alkalinising agents (e.g., sodium bicarbonate) may increase AMPH absorption

Dexamphetamine (d-amphetamine) and lisdexamfetamine:

D-amphetamine is a competitive inhibitor of DAT, NAT, and VMAT.

Lisdexamfetamine is a produg of d-amphetamine which is linked to the amino acid lysine.  It is cleaved to compounds d-amphetamine and inactive L-lysine.

Lisdexamfetamine is converted to dexamphetamine and L-lysine, not by cytochrome P450 enzymes metabolism, but by metabolism in blood primarily due to the hydrolytic activity of red blood cells. [PI]

 

Dexamphetamine (d-amphetamine): Immediate release (Dexedrine)

  • Onset of action – 20 to 60 minutes.
  • Duration – 3 to 6 hours.
  • Dosing: Starting 2.5 mg to 10 mg daily titrated at weekly increments of 2.5 mg to 5 mg to a maximum of 20 mg to 40 mg daily.

Lisdexamfetamine (Vyvanse)

  • Onset – approx 90 minutes.
  • Duration – 13 plus hours
  • Doses: 30 mg, 50 mg, 70 mg.
  • Dosing: 30 mg, 50 mg, 70 mg once daily.

Following administration, conversion of lisdexamfetamine to d-amphetamine occurs in approximately 1.5 hours, with duration from 1.5 to 13 hours in children and 2 to 14 hours in adults.

Food prolongs time to peak plasma concentration by approximately 1 hour.

The prodrug nature of Lisdexamfetamine, its rapid uptake from the gut, and its rate-limiting hydrolysis in the blood to produce active d-amphetamine have several important clinical implications.[Sharman and Pennick, 2014]

  • The profile of d-amphetamine delivery by Lisdexamfetamine underlies its long daily duration of action in relieving ADHD symptoms
  • Oral administration of Lisdexamfetamine results in systemic exposure to d-amphetamine that is proportional to the Lisdexamfetamine dose and that exhibits low intraindividual and interindividual variability.
  • Low potential for pharmacokinetic interactions
  • Less ‘drug-liking’ effects
  • Product information from TGA. 

Other Extended-release dexamphetamine formulations:

  • An extended-release mixed amphetamine salt formulation is a dual-pulse capsule preparation that includes both immediate- and extended-release beads. This formulation is not available in Australia.

Adderall:

  • Contains d-amphetamine and l-amphetamine salts in the ratio of 3:1.

Adverse effects:

  • Common: Insomnia, decreased appetite, dysphoria, irritability, tics
  • Rare: anxiety, depression, psychosis, mania
  • Cardiovascular (Rare): Cardiomyopathy, myocardial infarction, peripheral vascular disease, Raynaud disease, sudden cardiac death
  • Neurologic: Cerebrovascular accidents, seizure
  • Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis
  • Immunologic: Hypersensitivity reactions
  • Psychiatric: Psychotic disorder such as new or worsening psychotic or manic symptoms, behavior changes, or emotional lability

Drug Interactions: [Foong et al, 2018]

  • Concurrent use of amphetamine and serotonergic agents that inhibit CYP2D6 (Fluoxetine and Paroxetine) may increase amphetamine exposure and increase the risk of serotonin syndrome.
  • Caution with SSRIs and SNRIs.
  • Concurrent use of ascorbic acid and amphetamines may cause decreased amphetamine efficacy in patients.
  • Concurrent use of MAOIs is not recommended due to risk of serotonergic syndrome and hypertensive crisis.
  • Concurrent use of  pethidine, dextromethorphan, chlorpheniramine, brompheniramine, mepiridine, fentanyl can increase the risk of serotonin syndrome as they increase 5-HT. [Morphine, codeine, oxycodone and buprenorphine do not increase 5-HT, as they are weaker inhibitors of the serotonin transporter].
  • MDMA (Ecstasy) use may be overlooked and can be associated with severe serotonin syndrome.

References

Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine.

Kuczenski R, Segal DS, Cho AK, Melega W. Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. J Neurosci. 1995 Feb;15(2):1308-17.

Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication

Feinberg SS. Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication. J Clin Psychiatry. 2004 Nov;65(11):1520-4. 

The scoop on serotonin syndrome.

Foong AL, Patel T, Kellar J, Grindrod KA. The scoop on serotonin syndrome. Can Pharm J (Ott). 2018 May 30;151(4):233-239.

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