A. Therapeutic Utility

1. Stimulant - for attention deficit disorder (ADD)
2. Anorexic - induction of weight loss
3. Sympathomimetic (rare uses)
4. Euphoric - unclear role in medicine

B. Mechanism of Action

1. Increase Dopamine (and Norepinephrine, NE) release
2. Decrease Dopamine (and NE) uptake
3. Dopamine effects believed to be responsible for euphoria
4. MDMA (methylenedioxymethamphetamine, "ecstasy") causes vasopressin (ADH) release [4]

C. Specific Agents

1. Methamphetamine (Methedrine®)
2. Methylphenidate (Ritilin®)
3. Cocaine
4. Various abused agents including methamphetamine [9], MDMA ("ecstasy")
5. Ginseng (Panax ginseng)
6. Other agents, mainly for appetite suppression (see below)

D. Behavioral Effects

1. Euphoric alerting followed by depression
2. Tolerance and withdrawal symptoms occur
3. Thus, most stimulants are in fact addictive
4. May cause amphetamine psychosis with exacerbation of schizophrenia
5. Antipsychotic drugs (for example, haloperidol) with amphetamines lower seizure threshold

E. Clinical Uses

1. Attention Deficit Disorder
   1. Methylphenidate (Ritilin®) or Imipramine (less effective)
   2. Ritilin causes slight anorexia, but overall excellent drug
   3. Allows children to focus on particular stimulus
   4. May lead to hypersensitive children
2. Depression
   1. Mainly for severe depression with poor response to antidepressant agents
   2. May improve attention and reduce apathy
3. Obesity
   1. Dexfenfluramine (Redux®) is a non-stimulant serotonin blocker
   2. Fenfluramine is combination of R and S isomers, also used for appetite suppression
   3. Fenfluramine is often combined with anorectic agent phentermine ("Fen-Phen")
   4. Dextroamphetamine (Dexadrine®) is less useful due to side effects
   5. Many of these agents cause cardiac valve abnormalities, mainly insufficiency
   6. Fenfluramine and dexfenfluramine have been removed from the market
   7. Ephedra and ephedrine, stimulant alkaloids, are also be used for weight loss [6]
4. Narcolepsy
   1. Hyperactive REM state responds to amphetamines
   2. Effects of methylphenidate (Ritalin®) (5-15mg/d initially, 60mg max) last 2-3 hours
   3. Pemoline (Cylert®) 37.5mg initially, up to 112.5mg/d, is longer acting, less strong
   4. Modafinil (Provigil®) is another stimulant with some efficacy [7]
   5. Gamma hydroxybutyrate (GHB, sodium oxybate, Xyrem®) rapid acting hypnotic, approved for narcolepsy patients with moderate to severe cataplexy [8]

F. Overdose [1]

1. Acute toxicity similar to cocaine, with longer lasting effects
2. D-methamphetamine ("ice", "crystal") can be smoked
3. Increase elimination of drug by acidification of urine with ammonium chloride
4. High dose fenfluramines cause irreversible serotonergic neuronal (axon) loss in aminals [2]
5. MDMA ("ecstasy") causes antidiuretic hormone release and SIADH with hyponatremia [4,5]
6. Cocaine abuse associated with vasospasm including myocardial infarction [3]

G. Pulmonary Hypertension [2]

1. Use or fenfluramines is a major risk factor for development of pulmonary hypertension
2. This is idiopathic (primary) pulmonary hypertension (PPH)
3. There are no currently known predictors for development of PPH
4. Use of fenfluramines for >3 months within previous year had 10-20 fold increased risk

References

1. Stimulant Overdose. 1996. Med Let. 38(974):44
2. McCann UD, Seiden LS, Rubin LJ, Ricaurte GA. 1997. JAMA. 278(8):666
3. Hollander JE. 1995. NEJM. 333(19):1267
4. Henry JA, Fallon JK, Kicman AT, et al. 1998. Lancet. 351(9118):1784
5. Holden R and Jackson MA. 1996. Lancet. 347:1052
6. Shekelle PG, Hardy ML, Morton SC, et al. 2003. JAMA. 289(12);1537
7. Modafanil. 1999. Med Let. 41:30
8. Gamma Hydroxybutyrate for Narcolepsy. 2002. Med Let. 44(1145):103
9. Methamphetamine Abuse. 2004. 46(1188):62