However these were not
NECESSARILY associated with the drug. The potentially life threatening side
effects included hyponatremia, which appeared to be reversible when the patients
stopped taking the drug. A very few cases of vasculitis have also been
diagnosed. Cases of seizures and seizure like episodes in fluoxetine patients
have also been recorded. Some patients developed mania. An incidence of 0.2% has
been estimated for these episodes. It has been suggested that fluoxetine may be
associated with increased aggression and suicidal tendencies. It appears that in
some patients fluoxetine causes motor disturbances, which may be manifested
through aggression, irritability, and in extreme cases, even acting on already
suicidal thoughts often associated with depression. 15 out of 5000 New Zealand
fluoxetine patients have been found to have extrapyramidal effects associated
with the fluoxetine. Less serious effects are more common, and include anxiety,
nervousness, insomnia, drowsiness, fatigue, tremor, sweating, gastrointestinal
complaints, anorexia, nausea, diarrhea, and dizziness. Significant elevation of
hepatic enzymes also occurred in 0.5% of fluoxetine patients. A high incidence
of sexual dysfunction was also observed. 30% of patients suffered from this,
including decreased arousal and libido, as well as delay or loss of orgasmic
capacity. (3) In overdose fluoxetine is much safer than dothiepin. The main
danger comes from the seizures. (1) Adverse drug interactions include MAO
inhibitors, which can lead to severe and sometimes fatal reactions. Tryptophan
can cause increased agitation, restlessness and g. i. distress. Other
antidepressants should also be avoided, as fluoxetine greatly reduces their
clearance. Lithium interacts with fluoxetine, although unpredictably. In some
cases Lithium levels have been seen to fall, in some to rise, even to toxic
levels. CNS active drugs warrant caution when used concurrently with fluoxetine,
as it will reduce their clearance, and increase their effects. (3)
Pharmacokinetics Dothiepin Dothiepin is administered orally and is rapidly and
well absorbed. It is likely that in the gastrointestinal tract the absorption is
complete.
Peak concentrations in plasma are reached 3 hours after the drug is
taken. The average half-life of dothiepin is 22 hours, but it varies between 11
and 40 hours. (3) The oral clearance of dothiepin 1.4 1.kg-1h-1. The apparent
value of distribution is 45 1.kg-1, but is probably somewhat lower in reality.
There is not much variation in pharmacokinetics between healthy and depressed
patients. Dothiepin is largely metabolized in the liver, and just over half is
excreted in urine during the next 24 hours. Elimination is lower in liver
disease patients, however there is no clear clinical significance of this. (3)
Fluoxetine Fluoxetine is well absorbed in the gastrointestinal tract, whatever
the dosage form. Mean time to peak plasma concentration is approximately 6-8
hours. Fluoxetine is metabolized to norfluoxetine, which is also a powerful
antidepressant. (3) Flouxetine does not appear to have linear kinetics. Higher
doses result in disproportionately higher drug concentrations, most likely due
to saturation of the metabolic pathways in the liver, where fluoxetine is
metabolized. Fluoxetine has an average half-life of 48 to 72 hours, and it’s
metabolite, norfluoxetine has a half-life of 6.1 days. The high half life is the
result of plasma membrane binding and a high volume of distribution (42 1.kg-1.)
(3) As was mentioned above, fluoxetine is metabolized in the liver. 60-80% is
excreted in urine, and around 15% in feces. Renal impairment has very little
effect on the pharmacokinetics, but hepatic impairment severely decreases
clearance. (3)
Bibliography
(1) Psychopharmacology: The fourth generation of progress; Bloom F E, Kupfer D
J; Raven Press; 1995 (2) Basic and clinical pharmacology; Katzung B G; Appleton
and Lange; 1998 (3) Therapeutic drugs. Had to give this one back before I
finished with it, so no pub info. Need to look up on Library com
Bibliography
(1) Psychopharmacology: The fourth generation of progress; Bloom F E, Kupfer D
J; Raven Press; 1995 (2) Basic and clinical pharmacology; Katzung B G; Appleton
and Lange; 1998 (3) Therapeutic drugs. Had to give this one back before I
finished with it, so no pub info. Need to look up on Library com
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