Cardiovascular side effects

Compounds available in the United States are Hsted in Table 1. Whereas they vary in degree, all of them share similar HabiUties of cardiovascular side effects, the potential for central nervous system (CNS) stimulation, the development of tolerance, and abuse potential. AH, with the exception of ma2indol, are derivatives of phenethylamine. The introduction of an oxygen atom on the -carbon of the side chain tends to reduce CNS stimulant properties without decreasing the anorectic activity. Following the Federal Controlled Dmg Act of 1970, dmgs were classified into one of five schedules according to medical utiUty and abuse potential. 

A final area of research focuses on how the piU. can best be used by women. Physicians used to recommend pid-free hoHdays, but it is now known that there is no vaUd reason for this practice. Similarly, further research indicated that the U.S. EDA s restrictive guidelines for prescribing the piU. to women over the age of 35 are not justified, and those guidelines have been changed. EinaHy it is clear that cigarette smoking increases the risk of cardiovascular side effects, especially in women over 35 who utilize combination oral contraceptives. 

TNF was originally identified because of its cytotoxic activity against some tumor cell lines and its ability to induce hemorrhagic necrosis of solid tumors in various animal models. However, the clinical use of TNF as an anticancer drug has been so far limited by its severe cardiovascular side effects. Therefore, TNF treatment is limited to regional and local administration of high doses of TNF, often in combination with chemotherapy, as accomplished in isolated limb and isolated hepatic perfusion (ILP and IHP, respectively) [5]. In the case of ILP, typically metastases are treated, patients benefit from this procedure by salvage of limbs from a loss by amputation. 

Valproate sodium (Depacon) 15-20 mg/kg IV at 1.5-3 mg/kg per minute May have fewer cardiovascular side effects than other agents... 

EPS Sedation Anticholinergic Side Effects Cardiovascular Side Effects Seizure Effects/ QTc Prolongation... 

While this book was in production, Vioxx was withdrawn from the market due to unanticipated cardiovascular side effects. Whether this side effect is a specific liability of Vioxx, or a more general effect of all COX2 selective inhibitors remains unresolved at present. 

C Losa, MJ Alonso, JL Vila, F Orallo, J Martinez, JA Saavedra, JC Pastor. (1992). Reduction of cardiovascular side effects associated with ocular administration of metipranolol by inclusion in polymeric nanocapsules. J Ocular Pharmacol 8 191-198. 

Bupropion and venlafaxine may also be chosen because of their milder anticholinergic and less frequent cardiovascular side effects. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

Cigarette smoking Cigarette smoking increases the risk of cardiovascular side effects from hormonal contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes/day) and is quite marked in women more than 35 years of age. Women who use hormonal contraceptives should not smoke. 

There are of course many other targets which are known to mediate cardiovascular side-effects, for example, the serotonin 5HT2b receptor, but these are beyond the scope of this section and are reviewed in another chapter. 

Myelosuppression is the major side effect of paclitaxel. Alopecia is common, as is reversible dose-related peripheral neuropathy. Most patients have mild numbness and tingling of the fingers and toes beginning a few days after treatment. Mild muscle and joint aching also may begin 2 or 3 days after initiation of therapy. Nausea is usually mild or absent. Severe hypersensitivity reactions may occur. Cardiovascular side effects, consisting of mild hypotension and bradycardia, have been noted in up to 25% of patients. 

The most common side effects associated with aripiprazole include headache, nausea, dyspepsia, agitation, anxiety, insomnia, somnolence, and akathisia. Dose-related adverse events include somnolence and akathisia. Early clinical experience indicates that akathisia may be avoided by starting the medication at doses lower than 10 mg and increasing the dose slowly. Aripiprazole is not associated with significant sedation, anticholinergic side effects, weight gain, or cardiovascular side effects (Petrie et al. 1997). 

Cardiovascular side effects. Ziprasidone produced a mean QTc prolongation of 21 ms at maximal blood levels achieved with typical therapeutic doses. However, in all clinical trials, the rate of QTc intervals greater than 500 ms (considered a threshold for arrhythmia risk) did not differ from the rate associated with placebo (<0.1%). The QTc effect of ziprasidone is larger than that of other atypical antipsychotics but smaller than that of thioridazine. Blood levels of ziprasidone increased about 40% when ketoconazole (a metabolic inhibitor) was coadministered, and no change in QTc duration was detected. 

The nucleus of the one-time widely prescribed prescribed COX-2 inhibitor, rofecoxib, better known by its trade name Vioxx , actually comprises a butenolide rather than a classical heterocycle. The drug was withdrawn from the market at full flood due to an unexpectedly high incidence of adverse cardiovascular side effects. The compound is included at this point to emphasize the breadth of the SAR for COX-2 anti-inflammatory agents. Reaction of phenylacetic acid (35-1) with ethyl bro-moacetate in the presence of triethylamine leads to the formation of the ester (35-2). Treatment of that intermediate with a strong base generates a carbanion at the benzyhc position in an intramolecular reaction, this attacks the terminal ester carbonyl to yield the butenolide (35-3). Reaction of that compound with triflic anhydride converts the... 

This is a class IB drug used primarily for the emergency treatment of ventricular arrhythmias. It has little effect on sinus node automaticity but depresses normal and abnormal forms of automaticity in Purkinje fibres. It is generally ineffective against supraventricular and accessory pathway-induced (e.g. WPW syndrome) arrhythmias. Lidocaine is relatively safe and free from adverse cardiovascular side effects. It causes minimal cardiodepression, although high doses can cause heart block. The most common side effect is a dose-related CNS toxicity. It is given intravenously as a bolus of 1 mg-kg-1 followed by an infusion of 20-50 pg-kg-l-min-1. 

Stimulants increase the overall activity of the nervous system by boosting the release of various neurotransmitters such as dopamine, norepinephrine, and glutamate. The result is increased alertness, attention, and energy. Unfortunately, prescription stimulants can be highly addictive and cause cardiovascular side effects (increased heart rate, blood pressure, and irregular heart rate) as well as respiratory side effects (dilated airways and increased breathing rate). Taking stimulants repeatedly and in excessive doses can... 

Naproxen has fewer cardiovascular side-effects in comparison with the COX-2 selective inhibitor rofecoxib (Mukherjee et al., 2001). 

Side-effects Levomethadyl acetate induces opioid-type side-effects with respiratory depression, bradycardia and impairment of cardiac contractility (Wolven and Archer, 1976). The compound increases the QT-interval and may induce Torsade de pointes (Deamer et al., 2001). Because of the cardiovascular side effects (Q/T interval prolongation) Levomethadyl acetate was recently withdrawn from the market in most of the european countries. 

Ifenprodil and its back-up compound eliprodil were under clinical development by Synthelabo but have been withdrawn because of cardiovascular side-effects, (i.e. HERG channel inhibition (Soldo et al., 2000)). According to communications by the respective companies the development of CP-101,606 and Ro 25-6981 has also been halted. 

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