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Remeron more sedating at lower doses

At low concentrations, imipramine increases blood pressure by increasing the ionotrophic effect of norepinephrine on the myocardium and its vasoconstrictive effect on peripheral arterioles via its blockade of the norepinephrine uptake pump.

Imipramine shares this action with other norepinephrine reuptake inhibitors, including its active metabolites, desipramine, and the serotonin-norepinephrine reuptake inhibitor, venlafaxine.

The two primary principles underlying this series are: Binding affinity does not tell you what a drug will do but rather how much drug is needed to produce a specific effect--in other words, what drug level is needed to engage a site of action to a physiologically meaningful degree.This prolongation in turn sets the stage for escape ventricular beats, which can result in a fatal ventricular arrhythmia.The 10-fold separation between imipramine's affinity for the norepinephrine uptake pump and for the fast sodium channels means that an imipramine concentration can be achieved that produces an antidepressant response without causing delayed intracardiac conduction.However, the fact that the separation is only slightly more than 10-fold means that taking an overdose consisting of the entire amount contained in a typical 2-week prescription can result in a fatal arrhythmia.As I discussed in an earlier column, these pharmacological properties are the reason tertiary amine TCAs such as imipramine served as the blueprint for the development of subsequent antidepressants.General Bucky Turgeson in the Stanley Kubrick movie, Dr.Strangelove, was mighty proud of his aerial warriors and their B-52s.However, in contrast to desipramine and venlafaxine, imipramine at higher doses antagonizes its initial pressor effect on the cardiovascular system and can even cause orthostatic hypotension by blocking the alpha-1 adrenergic receptor resulting in decreased peripheral resistance.Since desipramine and venlafaxine do not block the alpha-1 adrenergic receptor over their clinically relevant dosing range, the likelihood and magnitude of their pressor effect simply increase as the dose of these drugs is increased.That fact explains why the tertiary amine tricyclic antidepressants (TCAs) can cause cardiac conduction disturbances and why they have a narrow therapeutic index.The cardiotoxicity of these drugs results from their ability to inhibit fast sodium channels and thus prolong intracardiac conduction.

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