Pharmacology venlafaxine

Pharmacology Venlafaxine and its active metabolite, 0-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. 

Consistent with its pharmacology, venlafaxine produces a similar type and incidence of sexual dysfunction as do the SSRIs. This effect can become apparent after several weeks of treatment at a stable dose. 

FIGURE 43.1 Pharmacologic treatment algorithm for full syndrome pediatric PTSD. Based on a snythesis of consensus data and clinical reports in the adult and child literature. The author hers no responsibility for the use of this guideline by third parties. SSRI, selective serotonin reuptake inhibitor NEE, nefaza-done SIB, self injurious behavior VLF, venlafaxine VPA, valproic acid. 

In cases of SSRI nonresponse, consideration should be given to using venlafaxine and nefazadone, as these agents appear to be safe and have consensus support for their use. Table 43.2 provides further detailed guidelines in matching specific pharmacological agents with PTSD symptom clusters. 

According to the Expert Consensus Panel for Mental Retardation Rush and Frances, (2000), the mainstays of the pharmacological treatment of acute mania or bipolar disorder in adults are anticonvulsant medications (divalproex, valproic acid, or carbamazepine) or lithium. Both divalproex or valproic acid and lithium were preferred treatments for classic, euphoric manic episodes. Divalproex or valproic acid was preferred over lithium and carbamazepine for mixed or dysphoric manic episodes and rapid-cycling mania. For depressive episodes associated with bipolar disorder, the addition of an antidepressant (SSRI, bupropion, or venlafaxine) was recommended. According to the Expert Consensus Panel, the presence of MR does not affect the choice of medication for these psychiatric disorders in adults. 

Social phobia also has a component of avoidance and has been successfully treated with the RlMAs brofaromine and moclobemide (Keck and McElroy 1997]. However, the SSRls and venlafaxine have also shown efficacy in social phobia (Gorman and Kent 1999 Keck and McElroy 1997], suggesting that further divisions of anxiety diagnostic categories may result from future pharmacological research. 

Venlafaxine and milnacipran are two members of a new class of antidepressants that have selective effects on the reuptake of both serotonin and noradrenaline—serotonin noradrenaline reuptake inhibitors (SNRIs). In theory, based on the findings of B. M. Baron and colleagues [1988 and of J. C. Nelson and colleagues (1991), the combination of these two pharmacological actions should be associated with superior efficacy either in terms of rapid onset of action or extra efficacy at the end of treatment. 

Few data are available regarding venlafaxine in overdose, but the drug s pharmacological profile suggests that it is safer than TCAs. In most of the reported cases to date, symptoms were not present. 

Treatment of GAD can be undertaken using a number of pharmacological agents. Benzodiazepines have been found to be superior to placebo in several studies and all benzodiazepines appear to be equally effective. However, side effects include sedation, psvchomotor impairment, amnesia and tolerance (Chapter 1). Recent clinical data indicate that SSRIs and SNRIs are effective in the treatment of acute GAD symptoms. Venlafaxine, paroxetine and imipramine have been shown to be effective antianxiety medications in placebo-controlled studies. Case studies also indicate the usefulness of clomipramine, nefazodone, mirtazapine, fluoxetine and fluvoxamine in GAD. Buspirone, a 5-HTla receptor partial agonist, has been shown to be effective in several placebo-controlled, double-blind trials (Roy-Byme and Cowley, 2002). Buspirone has a later onset of action than both benzodiazepines and SSRIs but with the advantage of being non-addictive and non-sedating. 

Venlafaxine is dependent on CYP 2D6 and 3A3/4 enzymes for its biotransformation and eventual clearance ( 138, 139 and 140). CYP 2D6 converts venlafaxine into 0-desmethylvenlafaxine (ODV), which is believed to have pharmacological activity comparable with the parent drug based on in vitro studies (141). Thus, this metabolite is to venlafaxine as norfluoxetine is to fluoxetine in that the half-life of ODV is longer than that of the parent drug, although it is only 12 hours versus 14 days for norfluoxetine. 

Nefazodone has some unusual pharmacological properties, not only inhibiting serotonin uptake, but also blocking the 5-HT 2a receptor. It may be that the antidepressant effect of serotonin agents is due to mediation of 5-HT transmission in the absence (or even the blockade) of 5-HT2a transmission. As a result of these actions, nefazodone is even more specific in terms of affecting a subtype of serotonin receptor than are the SSRIs or venlafaxine. 

The biotransformation of venlafaxine to its active metabolite, ODV, is dependent on CYP 2D6 (138, 306). The further elimination of ODV is dependent on CYP 3A3/4. Venlafaxine and ODV have approximate half-lives of 5 and 11 hours, respectively. Because venlafaxine and ODV have virtually identical pharmacological profiles, both are believed to contribute equally to the patient s overall response in terms of both efficacy and adverse effects ( 141). The 11-hour half-life of ODV is consistent with the fact that the immediate release formulation of venlafaxine is efficacious when administered twice daily. 

The sum of the concentration of venlafaxine and ODV is probably more important than their relative ratio. Thus, CYP 2D6 deficiency, which occurs in approximately 7% of Caucasians, has fewer clinical implications for venlafaxine than for drugs that are biotransformed by this isoenzyme to either centrally inactive metabolites (e.g., paroxetine) or metabolites that have a different pharmacological profile than the parent drug (e.g., TCAs). The increase in venlafaxine plasma levels is offset by a parallel decline in ODV levels such that the sum is the same. Nevertheless, a substantial inhibition of CYP 3A3/4 could result in a meaningful increase in both venlafaxine and ODV plasma levels, particularly in patients who are CYP 2D6 deficient. Such an increase would be expected to result in an increase in the incidence or severity of the known dose-dependent effects of venlafaxine mediated by its inhibition of the neuronal uptake pumps for serotonin and NE. 

In contrast to decreased libido seen with SSRIs and venlafaxine, concerns about priapism invariably arise when trazodone is discussed. This adverse effect is rare, occurring in only 1 of 6,000 treated male patients (456, 457). If the patient is informed of this possibility and discontinues the drug promptly, priapism usually resolves without further intervention. Although earlier persistent cases were treated surgically, this approach carries a 50% chance of permanent impotence pharmacological intervention via direct injections into the cavernous bulbosa is preferable ( 458, 459). Using this approach, the chance of permanent impotence is low and depends on the duration of symptoms before treatment (460). This latter fact is another reason to fully inform the male patient on trazodone, so that early detection and intervention can be implemented. 

Venlafaxine is converted by CYP 2D6 to ODV, which is subsequently cleared by CYP 3A3/4 ( 501). ODV has virtually the same in vitro pharmacology as venlafaxine. Thus, the total of venlafaxine plus ODV is believed to be the relevant concentration determining clinical effect ( 137). Theoretically, venlafaxine should be relatively impervious to even substantial CYP 2D6 inhibition because ODV levels would decrease proportionate to the increase in venlafaxine levels such that the total level would remain the same. In contrast, the inhibition of CYP 3A3/4 would be potentially more clinically relevant because it should decrease ODV clearance and thus increase total levels. Nevertheless, such an interaction would not be expected to do more than increase the usual dose-dependent adverse effects of venlafaxine because of its wide therapeutic index. 

Holliday SM, Benfield P Venlafaxine. A review of its pharmacology and therapeutic potential in depression. Drugs 1995 49(2) 280. [PMID 7729333]... 

The time spent reviewing the pharmacology of venlafaxine, mirtazapine and nefazodone was just right. ... 

Fluoxetine (Prozac /Lilly), paroxetine (Paxil /GlaxoSmithKilne), and sertraline (Zoloft /Pfizer) are selective serotonin reuptake inhibitors (SSRIs) and are useful in the treatment of depression. These agents potentiate the pharmacological actions of the neurotransmitter serotonin by preventing its reuptake at presynaptic neuronal membranes. In addition to its SSRI properties, venlafaxine (EfFexor /Wyeth-Ayerst) also appears to be a potent inhibitor of neuronal norepinephrine reuptake and a weak inhibitor of dopamine reuptake thereby enhancing the actions of these neurotransmitters as well. Venlafaxine is indicated for use in anxiety and depression. 

Subsequently, the UK Committee on Safety of Medicines issued guidance for practitioners, indicating that with the exception of fluoxetine, the benefit-harm balance of SSRIs and venlafaxine in depressed children and adolescents was unfavorable (27). A similar conclusion was drawn concerning mirtazapine. It is, however, puzzling that the therapeutic effects of fluoxetine should be quite so different from compounds that are similar pharmacologically. One important issue might be the relevance of regulatory trials of antidepressants to real-world treatment. Placebo-controlled trials in depression... 

This patient developed features of drug dependence. Such reactions are unusual but might be related to the ability of venlafaxine to potentiate dopamine function at high doses. This pharmacological property characterizes many drugs that are misused for their euphoriant properties. 

Rflc-venlafaxine 10 and its sila analogue rac-11 have similar physicochemical properties (pi Ca = 9.7, log P = 3.1 in n-octanol/water, log P = 0.9 at pH 7.4) indicating that venlafaxine and sila-venlafaxine could have a similar brain penetration profile. The in vitro pharmacological studies of venlafaxine, sila-venlafaxine and their enantiomers (used as hydrochlorides) for their efficacy in monoamine reuptake inhibition demonstrated differences in activity and also in inhibition profile (06JOM(691)3589, 06OM1188). With respect to serotonin, noradrenaline and dopamine reuptake inhibition potency these... 

Summary Novel potential o ligands of the l,4 -silaspiro[tetralin-l,4 -piperidine] type (compounds lb - 4b, isolated as hydrochlorides) and rac-sila-venlafiixine (rac-5b, a silicon analog of the serotonin/noradrenaline leuptake inhibitor roc-venla xine (rac-5a)) were synthesized. In addition, the sila-venlafaxine enantiomers (i )-5b and (S)-5b and the sila-venla xine derivatives / ac-6-HCl and rac-T-HCl were prepared. Compounds 3b-HCl and rac-Sb-HCl were structurally characterized by single-crystal X-ray diffraction, and rac-Sa, rac-Sh, rac-6, and rac-7 were pharmacologically characterized. 

We report here on (1) the synthesis of the silicon-based potential a ligands lb - 4b (isolated as the hydrochlorides), (ii) the synthesis of rac-sila-venlafaxine (rac-Sb), (iii) the preparation of the slla-venlafaxine enantiomers (if)-5b and (S)-5b via resolution of rac-Sh, (iv) the synthesis of the sila-venlafaxine derivatives rac-6 and rac-7, (v) the crystal structure analyses of 3b-HCl and rac-5b HCl, and (vi) the pharmacological characterization of rac-5a, rac-5b, rac-6, and rac-7. Preliminary results of the studies reported here have already been presented elsewhere [6, 7]. 

The older tricyclic agents show less than a ten-fold selectivity in inhibiting noradrenaline over that for 5-HT (e.g. desipramine, imipramine, nortriptyline) through amitryptyline. which shows virtually no selectivity, to trazodone, zimelidine and clomipramine, which are somewhat 5-HT selective. The newer Serotonin-Selective Reuptake Inhibitors (SSRIs) show a higher selectivity for inhibition of 5-HT reuptake in the brain, and have a different pharmacology. Examples clinically used include citalopram, fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline, trazodone and venlafaxine. Experimental agents include 6-nitroquipazine, alaproclate, litoxetine, indatraline and p-CIT. 

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