Download Antidepressant

Pharmacology II
lec.3
Antidepressant drugs
Depression is characterized by intense feeling of sadness, hopelessness,
inability to experience pleasure, changes in sleep patterns and appetite,
loss of energy, and suicidal thoughts. Mania is characterized by the
opposite behavior that includes rapid thought and speech patterns,
extreme self-confidence, and impaired judgment.
Mechanism of Antidepressant Drugs
Most antidepressant drugs potentiate, either directly or indirectly, the
actions of in the brain. This led to the amine theory, which states that
depression is due to a deficiency of monoamines, such as norepinephrine
and serotonin, at certain sites in the brain. Conversely, the theory states
that mania is caused by an overproduction of these neurotransmitters. The
pharmacologic effects of any of the antidepressant and antimania drugs
on neurotransmission occur immediately, whereas the therapeutic
response occurs over several weeks. Decreased the uptake of
neurotransmitter is only an initial effect of the drugs, which may not be
directly responsible for the antidepressant effects. It has been proposed
that presynaptic inhibitory receptor densities in the brain decrease over a
2- to 4-week period with antidepressant drug use. This down-regulation
of inhibitory receptors permits greater synthesis and release of
neurotransmitters into the synaptic cleft leading to a therapeutic response.
1-
selective serotonin reuptake inhibitors (SSRI):
Include: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine,
and sertraline.
These drugs specifically inhibit serotonin reuptake. This contrasts with
the tricyclic antidepressants that nonselectively inhibit the uptake of
norepinephrine and serotonin. Both of these antidepressant drug classes
exhibit little ability to block the dopamine transporter. Moreover, the
SSRIs have little blocking activity at muscarinic, α--adrenergic, and
histaminic H1 receptors. Therefore, common side effects that associated
with tricyclic antidepressants, such as orthostatic hypotension, sedation,
dry mouth, and blurred vision, are not commonly seen with the SSRIs,
therefore they are considered as the drugs of choice in treating
depression.
1
Actions
The SSRIs block the reuptake of serotonin, leading to increased
concentrations of the neurotransmitter in the synaptic cleft and, increased
postsynaptic neuronal activity. Antidepressants, including SSRIs,
typically take at least 2 weeks to produce significant improvement in
mood, and maximum benefit may require up to 12 weeks or more. Note:
These drugs do not usually produce central nervous system (CNS)
stimulation or mood elevation in normal individuals.
Therapeutic uses
1- depression.
2- Obsessive- compulsive disorder (fluvoxamine is effective).
3- Panic disorder.
4- Generalized anxiety disorder; social anxiety disorder.
5- Premenstrual syndrome.
6- Bulimia nervosa (fluoxetine is effective).
Pharmacokinetics
All of SSRIs are well absorbed after oral administration. Food increases
absorption of sertraline only. Metabolism by P450-dependent enzymes and
glucuronide or sulfate conjugation occur extensively. Fluoxetine has
longer half life (50 hrs) and available as a sustained release preparation
allowing once weekly dosing. Fluoxetine and paroxetine are potent
inhibitors of a hepatic cytochrome p450 responsible for the elimination of
TCA drugs, neuroleptic, some antiarrhythmic, β-adrenergic antagonist
drugs.
Adverse effects
1- nausea, vomiting, diarrhea.
2- Headache, anxiety.
3- Sweating.
4- Weakness and fatigue.
5- Sexual dysfunction.
6- Changes in weight.
7- Sleep disturbances.
2
2Serotonin-Norepinephrine Reuptake Inhibitors
Venlafaxine and duloxetine selectively inhibit the re-uptake of both
serotonin and norepinephrine. These agents may be effective in treating
depression in patients in whom SSRIs are ineffective, in addition to treat
the painful symptoms that associate depression such as backache and
muscle aches. The SNRIs, unlike the tricyclic antidepressants, have little
activity at adrenergic, muscarinic, or histamine receptors and, thus
associated with less side effects.
A. Venlafaxine
Venlafaxine is a potent inhibitor of serotonin reuptake and, at medium to
higher doses, is an inhibitor of norepinephrine re-uptake. It is also a mild
inhibitor of dopamine reuptake at high doses. Venlafaxine has minimal
inhibition of the cytochrome P450. The most common side effects of
venlafaxine are nausea, headache, sexual dysfunction, dizziness,
insomnia, sedation, and constipation. At high doses, there may be an
increase in blood pressure and heart rate.
B. Duloxetine
Duloxetine inhibits serotonin and norepinephrine reuptake at all doses. It
is extensively metabolized in the liver to numerous metabolites.
Duloxetine should not be administered to patients with hepatic
insufficiency. Metabolites are excreted in the urine. Food delays the
absorption of the drug. Duloxetine is highly bound to plasma protein.
Gastrointestinal side effects are common including nausea, dry mouth,
and constipation. Insomnia, dizziness, somnolence, and sweating are also
seen. Sexual dysfunction also occurs along with the possible risk for an
increase in either blood pressure or heart rate.
Atypical Antidepressants
They are not more efficacious than the tricyclic antidepressants or SSRIs.
A. Bupropion
This drug acts as a weak dopamine and norepinephrine reuptake inhibitor
to alleviate the symptoms of depression. Its short half-life may require
more than once-a-day dosing or the administration of an extended-release
formulation. Bupropion attenuates the withdrawal symptoms for nicotine
in tobacco users trying to quit smoking. Side effects may include dry
3
mouth, sweating, nervousness, tremor and an increased risk for seizures
at high doses.
B. Mirtazapine
This drug enhances serotonin and norepinephrine neurotransmission by
its ability to block presynaptic α2 receptors. It is a sedative because of its
potent antihistaminic activity, but it does not cause the antimuscarinic
side effects of the tricyclic antidepressants, or interfere with sexual
functioning, as do the SSRIs. Increased appetite and weight gain
frequently occur.
C. Nefazodone and trazodone
These drugs are weak inhibitors of serotonin reuptake. They block
postsynaptic 5-HT2A receptors. With chronic use, these agents may
desensitize 5-HT1A presynaptic autoreceptors and, thereby, increase
serotonin release. Both agents are sedating, probably because of their
potent H1-blocking activity. Nefazodone has been associated with the
risk for hepatotoxicity.
Tricycli antidepressants(TCAs):
Include:
imipramine,
amitriptyline,
clomipramine,
doxepin,
trimipramine, desipramine, nortriptyline, protriptyline, Maprotiline and
amoxapine.
Mechanism of action
1. Inhibition of the neuronal reuptake of norepinephrine and serotonin
into presynaptic nerve terminals causing increased concentrations of
monoamines in the synaptic cleft, and resulting in antidepressant effects.
Maprotiline and desipramine are selective inhibitors of norepinephrine
reuptake.
2- Blocking of receptors: TCAs also block serotonergic, α-adrenergic,
histaminic, and muscarinic receptors. However, actions at these receptors
are probably responsible for many of the untoward effects of the TCAs.
Amoxapine also blocks the D2 receptor.
Actions:
1- mood elevation.
2- Improvement of mental alertness.
4
3- Increase physical activity.
4- The onset of mood elevation is slow requiring 2 weeks or longer.
5- Do not produce CNS stimulation or mood elevation in normal
individuals.
6- Physical and psychological dependence has been rarely reported.
7- These drugs can be used for prolong treatment of depression.
Therapeutic uses
1- treatment of moderate to sever major depression.
2- Panic disorder.
3- Imipramine has been used to control bed-wetting in children (older
than 6 years) but with caution because of the inducement of cardiac
arrhythmias.
4- Treatment of migraine headache and chronic pain.
Pharmacokinetics:
TCAs are well absorbed upon oral administration; and because of their
lipophilic nature, are widely distributed and readily penetrate into CNS.
Have long half life for e.g. 4-17 hrs for imipramine. The initial period of
treatment is typically 4-8 weeks. The dose can be gradually reduced
unless relapse occurs. TCAs are metabolized in the liver and excreted in
urine.
Adverse effects
1- Antimuscarinic effects: blockade of Ach receptors leads to
blurred vision, xerostomia (dry mouth), urinary retention,
constipation, aggravation of glaucoma and epilepsy.
2- Cardiovascular: increased catecholamine activity results in
cardiac overstimulation, slowing of atrioventricular conduction.
3- Orthostatic hypotension and reflex tachycardia: due to αadrenergic receptors blocking.
4- Sedation: during the first several weeks.
5- Weight gain and sexual dysfunction.
6- Narrow therapeutic index; 5-6 fold the maximal daily dose may be
lethal.
Monoamine oxidase inhibitors(MAOIs)
5
Monoamine oxidase (MAO) is a mitochondrial enzyme found in nerve
and other tissues such as gut and liver. In the neuron MAO functions
as a safety valve that deaminate and inactivate any excess
neurotransmitter molecules ( norepinephrine, dopamine and
serotonin).
MAOIs may reversibly or irreversibly inactivate the enzyme,
permitting neurotransmitter molecules to escape degradation and
therefore to accumulate within the presynaptic neuron and leak into
the synaptic space.
MAOIs include: phenelzine, isocarboxazide and tranylcypromine.
Uses of MAOIs is now limited because of dietary restriction required
in patients taking MAOIs.
Mechanism of action
Most MAOIs such as isocarboxazide and phenelzine form stable
complexes with MAO enzyme causing irreversible inactivation. This
results in increased stores of norepinephrine, serotonin and dopamine
within the neuron and subsequent diffusion of excess neurotransmitter
into synaptic cleft.
Actions
Although MAO is fully inhibited after several days of treatment, the
antidepressant action of MAOI like that of TCA and SSRIs is delayed
several weeks. Phenelzine and tranycypromine have mild
amphetamine like stimulant effect.
Therapeutic use
1- used in depressed patients who are unresponsive or allergic to
TCA or who are experience strong anxiety.
2- Patients with low psychomotor activity may benefit from the
stimulant properties of MAOIs.
3- Treatment of phobic states.
4- Atypical depression.
Pharmacokinetics
These drugs are well absorbed orally, but antidepressant effects
requires at least 2-4 weeks of treatment. When switching antidepressant
agent a minimum of 2 weeks of delay must be allowed after termination
6
of MAOI therapy and initiation another antidepressant. MAOIs are
metabolized and excreted rapidly in urine.
Adverse effects
1- sever and often unpredictable side effects limit the widespread use
of MAOIs. For example tyramine containing food such as aged
cheese, chicken liver, beer and red wines, is nortmally metabolized
by MAO in the gut. Tyramine causes the release of large amounts
of stored catecholamines from nerve terminals resulting in
headache, tachycardia, nausea, hypertension, cardiac arrhythmia;
patients must be educated to avoid tyramine containing food.
2- Other side effects are drowsiness, orthostatic hypotension, blurred
vision, dry mouth, dysurea and constipation. MAOIs and SSRIs
should not be coadministered due to the risk of life threatening
"serotonin syndrome ".
Treatment of Mania and Bipolar Disorder
Lithium salts are used prophylactically for treating manic-depressive
patients and in the treatment of manic episodes and, thus, is considered as
mood stabilizer. Lithium is believed to attenuate signaling via receptors
coupled to the phosphatidylinositol bisphosphate (PIP2) secondmessenger system. Lithium interferes with the resynthesis (recycling) of
PIP2, leading to its relative depletion in neuronal membranes of the CNS.
PIP2 levels in peripheral membranes are unaffected by lithium. Lithium
salts have therapeutic index are extremely Low comparable to those of
digitalis. Common adverse effects may include headache, dry mouth,
polydipsia, polyuria, polyphagia, gastrointestinal distress (give lithium
with food), tremor, dizziness, fatigue, dermatologic reactions, and
sedation. Adverse effects due to higher plasma levels may include ataxia,
slurred speech, coarse tremors, confusion, and convulsions. Several
antiepileptic drugs, including carbamazepine, valproic acid, and
lamotrigine, have been identified as mood stabilizers and have been used
in the treatment of bipolar disorder. The atypical antipsychotics
(risperidone, olanzapine, ziprasidone, aripiprazole, and quetiapine) also
used in the management of mania.
7