Dothiepin Vs. Fluoxetine (Mechanism Of
Action And Pharmacodynamics)
Comparison Between Mechanism of Action and Pharmacodynamics of Dothiepin and
Fluoxetine Description of medicines Mechanism of action and pharmacodynamics
Dothiepin Dothiepin is a tricyclic antidepressant. It acts by promoting the
effectiveness of several amines (dopamine, norepinephrine, and
5-hydroxytryptamine, which is also known as 5HT and serotonin). It functions by
inhibiting their reuptake at the terminals of nerve cells, thus leading to their
prolonged presence at the synaptic cleft and an increased effect on the
neuron.(1) The reuptake pumps for the above amines are responsible for reducing
the concentration of these amines. Dothiepin works by blocking the pumps.
According to the amine hypothesis, a decreased concentration of the amines and
the resulting decrease in amine dependant synaptic transmission is associated
with depression, therefore an increase in the above would help relieve the
symptoms of depression. (2) Dothiepin has other actions as well. It reduces
norepinephrine induced CAMP formation in the brain, as well as inhibiting the
uptake of 5HT into platelets. It also has some anticholinergic and
antihistaminic activity.(3) Dothiepin begins to take effect after approximately
2-3 weeks. Usual daily doses of Dothiepin range from 75mg to 200mg in the more
severe cases. (2) Fluoxetine Fluoxetine belongs to a group of antidepressants
known as the SSRI’s, or Selective serotonin reuptake inhibitors. It functions is
similar to that of dothiepin above. It also acts as a reuptake inhibitor, but is
highly selective. It only inhibits 5HT reuptake, and lacks many of the less
useful functions of dothiepin, such as the antihistaminic properties. (1) As
above the result in increase in the presence of serotonin at the synaptic cleft
results in a decrease in many symptoms of depression. Fluoxetine does however
have some side effects including nausea, tremors, loss of libido and in some
cases decreased sexual function. (2) It is also possible that it may have an
effect on dopamine function. In some cases it also reduces sleep efficiency. (3)
Daily doses of Fluoxetine range between 10mg and 60mg.
However it has been found
that effectiveness does not appear to be strongly related to dose. 20mg is as
affective as 40mg, and there is some evidence to suggest that higher doses may
be even less effective. However the lower doses result in fewer and less sever
adverse effects.(3) Adverse effects or adverse drug interactions Dothiepin
Adverse effects of dothiepin range from potentially life threatening to mildly
discomforting. Fatalities associated with dothiepin include cardiac failure,
neonatal cardio-respiratory failure, myocardial infarction, arrhythmia, cardiac
arrest, ventricular fibrillation, stroke, congenital heart disease, haematemesis,
aplastic anemia, leukopenia, hepatorenal syndrome, cholestatic jaundice, coma,
neuroleptic malignant syndrome, aggravated Parkinson’s disease, intrauterine
death, renal failure, respiratory arrest. These however are very rare. (1) Other
severe side effects include hepatitis, inappropriate ADH secretion, hypomania,
and convulsions. Psychotic manifestations, e.g. paranoid delusions, may be
brought about or worsened if already present. These symptoms are also very
uncommon, though less life threatening than those listed above.(3) The less
dangerous side effects are a bit more common, found in many patients,
particularly those on higher doses of the drug. These include dry mouth,
tachycardia, constipation, drowsiness, sweating, nausea, vomiting, diarrhea,
tremor, rashes, and interference with sexual function.(3) The greatest dangers
in overdose stem from convulsions, and the cardiac and respiratory effects
listed above. (3) Adverse drug interactions include MAO inhibitors and SSRI's as
concurrent administration may lead to increased plasma tricyclic levels. CNS
depressants, including alcohol will also have an increased effect when taken in
conjunctions with dothiepin. Anesthetics may increase the risk of arrhythmia.
Antihypertensive agent activity may be reduced by dothiepin. Barbiturates may
decrease the serum concentration of dothiepin, while methyl phenidate may
increase it. Smoking may reduce the serum concentration of dothiepin by
increasing its metabolism. (1) Fluoxetine Fluoxetine appears to have a lower
incidence of adverse reactions, and these appear less severe than those
associated with dothiepin. (2) Up to 1990 a total of 11 deaths that may be
associated with fluoxetine were recorded in patients.
