FREE ESSAY ON DOTHIEPIN VS. FLUOXETINE (MECHANISM OF ACTION AND PHARMACODYNAMICS)

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. 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