Benzodiazepines with a half-life of less than 24 hours include alprazolam, bromazepam, brotizolam, flunitrazepam, loprazolam, lorazepam, lormetazepam, midazolam, nitrazepam, oxazepam, and temazepam. The resultant equivalent dose is then gradually reduced. The consensus is to reduce dosage gradually over several weeks, e.g. 4 or more weeks for diazepam doses over 30 mg/day,
with the rate determined by the persons ability to tolerate symptoms. The recommended reduction rates range from 50% of the initial dose every week or so,
to 10-25% of the daily dose every 2 weeks. For example, the reduction rate used in the Heather Ashton protocol calls for eliminating 10% of the remaining dose every two to four weeks, depending on the severity and response to reductions with the final dose at 0.5 mg dose of diazepam or 2.5 mg dose of chlordiazepoxide. For most people, discontinuation over 4–6 weeks or 4–8 weeks is suitable. A prolonged period of reduction for longer than six months should be avoided to prevent the withdrawal process from becoming a "morbid focus" for the person. Duration
After the last dose has been taken, the acute phase of the withdrawal generally lasts for about two months although withdrawal symptoms, even from low-dose use, can persist for six to twelve months gradually improving over that period, however, clinically significant withdrawal symptoms may persist for years, although gradually declining. A clinical trial of patients taking the benzodiazepine alprazolam for as short as eight weeks triggered protracted symptoms of memory deficits which were still present up to eight weeks after cessation of alprazolam.
Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations. There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification, not unlike the hepatic formation of cocaethylene from cocaine and ethanol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity. Pharmacology
Pharmacodynamics
Methylphenidate primarily acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It is a benzylpiperidine and phenethylamine derivative which also shares part of its basic structure with catecholamines. Methylphenidate is a psychostimulant and increases the activity of the central nervous system through inhibition on reuptake of the neurotransmitters norepinephrine and dopamine. As models of ADHD suggest, it is associated with functional impairments in some of the brains neurotransmitter systems, particularly those involving dopamine in the mesocortical and mesolimbic pathways and norepinephrine in the prefrontal cortex and locus coeruleus. Psychostimulants like methylphenidate and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems. When reuptake of those neurotransmitters is halted, its concentration and effects in the synapse increase and last longer, respectively. Therefore, methylphenidate is called a norepinephrine–dopamine reuptake inhibitor.