Antidepressants drugs

Pharmacology
Department
Lecturer Genny Dominguez

BIBLIOGRAPHY
Goodman and Gilmans. The
pharmacological basis of therapeutics.
Basic and Clinical Pharmacology. Bertram
G. Katzung.
Pharmacology. H. P Rang, M. M. Dale, J.
M. Ritter, P. K. Moore.
Pharmacology. 3rd edition. Lippincotts.

SUMMARY
Antidepressants.
1. Tricyclic antidepressants.
2. Selective serotonin
reuptake inhibitors.
3. Serotonin/Norepinephrine
reuptake inhibitors.
4. Monoamine oxidase
inhibitors.
5. Atypical antidepressants.
It is the most common of the affective
disorders.
It may range from a very mild condition,
bordering on normality, to severe
(psychotic).
Its a major cause of disability and
premature death.
In addition to the significant suicide risk,
depressed individuals are more likely to die
from other causes, such as heart disease or
cancer.
Depression
Depression
Emotional symptoms:
Misery, apathy, and
pessimism, hopelessness.
Low self esteem.
Feelings of guilt, inadequacy
and ugliness.
Indecisiveness and loss of
motivation.
Biological symptoms:
Retardation of thought and
action.
Loss of libido.
Sleep disturbance and loss of
appetite.
Depression
The clinical syndromes are:
Unipolar depression:
Reactive depression
Endogenous depression.
Bipolar depression:
Manic depressive psychosis.
Monoamine theory for depression
Theory: Reduced monoamine transmission
(NA &/or 5HT) causes depression.
Evidence
Reserpine, which depletes neuronal monoamine
stores, causes depression.
Methyldopa, which reduces CNS NA release,
causes depression.
Note: Measurements of monoamine levels do
not clearly support the hypothesis.
Drugs which enhance monoamine transmission
improve depression.
Processes to remaind
The release of a monoamine
neurotransmitter from a nerve terminal.
Inhibition of transmitter release by an
inhibitory pre-synaptic receptor.
Elimination of neurotransmitter from the
synaptic cleft by:
a high affinity reuptake mechanism.
A low affinity reuptake mechanism.
Passive diffusion.
Release of Noradrenaline

1
-adrenoceptor
NA
NA
- NA is released in response to
depolarization of sympathetic
nerves.

- NA activates
1
-adrenoceptors
of the target tissue.

Release of Noradrenaline

1
-adrenoceptor
NA
NA

2
-adrenoceptor
_
- NA also activates
2
-
adrenoceptors of the
nerve terminal.

-
2
-adrenoceptors inhibit
release of NA.

- This a negative feed-
back system.

NOTE: THIS NOT A
SYSTEM FOR THE RE-
UPTAKE OF NA
Re-uptake of Noradrenaline

1
-adrenoceptor
NA
NA
NA
Uptake 1
Uptake 2
- NA is released in large
amounts from sympathetic
nerves, and requires to be
cleared from the synapse by
two uptake systems and by
diffusion in the circulation:

Uptake 1: is a high affinity, low
capacity system that permits
NA uptake by the nerve
terminal.

Uptake 2: is a low affinity, high
capacity system that permits
NA uptake into the target
tissue.
Noradrenaline Reuptake 1 Inhibitors

1
-adrenoceptor
NA
NA
NA
Uptake 1
Uptake 2
Anti-depressants are widely
used in medicine, and include
drugs such as amitriptyline

They stimulate nor-adrenergic
transmission within the CNS by
inhibiting the uptake 1 system,
which increases the synaptic
concentration of NA.
Amitriptyline
Antidepressants groups
Tricyclic antidepressants (TCAs).
Serotonin-selective reuptake inhibitors
(SSRIs).
Serotonin/Norepinephrine reuptake
inhibitors (SNRIs).
Non-selective MAOIs.
Atypical antidepressants.
Tricyclic antidepressants
(TCAs)
Tertiary amines:
Amitriptyline
Imipramine
Clomipramine
Doxepin
Trimipramine

Secondary amines:
Desipramine
Nortriptyline
Amoxapine
Aprotiline
Protriptyline
Tricyclic antidepressants
Amitriptyline, imipramine, clomipramine are non-
selective inhibitors of both NA and 5HT.
Nortriptyline is moderately selective for NA.
Onset of antidepressant effect in 2-4 weeks, whereas
the receptor blocking effects are immediate.
Effective against unipolar depression, both reactive and
endogenous.
The drugs are taken orally and have a T1/2 of 10-20 h.
They are best suited to the treatment of mild or
moderate depression.
In overdose, these drugs are hazardous.
TCAs are also inhibitors of:
Muscarinic cholinergic receptors:
Dry mouth, mydriasis, blurred vision, tachycardia,
constipation, urinary retention.
Histamine H
1
receptors:
Sedation may help disturbed sleep if taken at night.
Cardiac K
+
channels:
In overdose, these drugs may cause life-threatening
ventricular arrhythmias.

Tricyclic antidepressants provide effective treatment for
neuropathic pain (results from damage to or dysfunction of
the peripheral or CNS, rather than stimulation of pain
receptors).
TCAs actions
Elevate mood (the onset is slow 2 weeks).
Improve mental alertness.
Increase physical activity.
Reduce morbid preocupation in individual with major
depression.
Physical and psychological dependence (should be
slowly withdrawal).
Can be used for prolonged treatment of depression.
TCAs therapeutic uses.
Severe major depression.
Panic disorders.
To control bed-wetting in
children (older than 6
years) by causing
contraction of the internal
sphincter of bladder.
Chronic pain (neuropathic
pain) amitriptyline.
PANIC
TCAs ADR
Antimuscarinic effects: Blurred vision,
Xerostomia (dry mouth), Urinary
retention, Constipation, Aggravation of
glaucoma and epilepsy.
Increased catecholamine activity:
Cardiac over stimulation (overdose).
Block adrenergic receptor: Orthostatic
hypotension and reflex tachycardia.
Block histamine H
1
receptors: Sedation.
Weight gain.
Sexual dysfunctions (erectile
dysfunction in men, anorgasmia in
women).
TCAs interactions
TCA
Direct-acting
Adrenergic
drugs
MAOI
Indirect-acting
Adrenergic drugs
Ethanol
CNS depressants
Toxic sedation
Mutual enhancement:
Hypertension
Hyperpyrexia
Convulsions
Coma
Block effects of
indirect-acting
symphatomimetic
drugs.
Potentiate effects of
biogenic amine drugs
by preventing their
removal from the
synaptic cleft.
TCAs Precautions
Should be used with caution in manic-
depressive patients, because they may
unmask maniac behaviour.
They have narrow therapeutic index: 5 to 6
fold the maximal daily dose of imipramine can
be lethal.
Serotonin-selective reuptake
inhibitors (SSRIs)
These drugs include fluoxetine, paroxetine, sertraline,
citalopram, escitalopram and fluvoxamine.
They are highly selective for 5HT reuptake.
They are taken orally and have a very long half life
(>24h).
SSRIs cause less anti-muscarinic effects than tricyclic
antidepressants.
They are much safer than tricyclic antidepressants in
overdose.
They appear to cause an increased suicidal risk in
children and teenagers, and so are avoided in these
groups.
SSRIs
The onset of the
antidepressant effect takes 2-4
weeks.
Maximum benefit may require
twelve weeks or more.
3 months
2 weeks
SSRIs Therapeutic uses.
They are effective in a variety of
psychiatric disorders:
Depression.
Obsessive-compulsive disorder (the
only indication of fluvoxamine).
Panic attacks.
Anxiety.
Premenstrual dysphoric disorder.
Bulimia nervosa.
SSRIs
Fluoxetine: Longer half-life (fifty hours).
Fluoxetine and paroxetine are inhibitors of the cytochrome
P450 responsible for the elimination of TCA, neuroleptics,
antiarrythmics and -adrenergic antagonist drugs.
Renal excretion, except paroxetine and sertraline (fecal).
Hepatic impairment (dosages should be adjusted).
SSRIs Adverse effects
They have fewer and less severe adverse effects than the
TCA and MAOIs.
GI effects: Nausea and diarrhoea.
Anxiety.
Weakness.
Sleep disturbances: Drowsiness, insomnia; Paroxetine and
fluvoxamine are sedating, may be useful in patient who have
difficulty sleeping.
Sexual dysfunction: Loss of libido, delayed ejaculation and
anorgasmia, if the SSRIs induce sexual dysfunction should
be replaced by bupropion or mirtazapine.
Rarely, SSRIs may precipitate aggressive or violent
behaviour.
SSRIs, Overdoses and interactions.
Fluoxetine: Seizures.
In combination with MAOIs, they may
cause the serotonin syndrome, which
comprises, tremor, hyperthermia and
cardiovascular collapse.
Serotonin/Norepinephrine
reuptake inhibitors (SNRIs)
These drugs inhibit the reuptake of both
serotonin and norepinephrine.

They include:

Duloxetine
Venlafaxine

SNRIs
May be effective in treating depression
in patients in which SSRIs are
ineffective.
Effective in depression accompanied by
chronic painful symptoms (neuropathic
pain), backache and muscle aches, this
pain is in part modulated by serotonin
and norephinephrine in the CNS.
Venlafaxine is used mainly in the
elderly. It is less sedative and has
fewer antimuscarinic effects than the
tricyclic antidepressants.
SSRIs
Monoamine oxidase
Monoamines are eliminated by enzymatic
degradation.
There are two principle enzymes:
Monoamine oxidase (MAO).
Catechol-O-methyltransferase (COMT).
There are two MAO isoenzymes:
MAO-A
MAO-B
The two enzymes have a different distribution
within the body:
MAO-A is found in the CNS, liver and gut wall.
MAO-B is found in the CNS alone.
Monoamine oxidase and its inhibitors
There are differences in the substrate
specificity of MAO-A and MAO-B:
MAO-A oxidises NA, 5HT, dopamine and
tyramine.
MAO-B oxidises dopamine and tyramine.
Inhibitors of monoamine oxidase divide into
two groups:
Non-selective MAO inhibitors (used in
depression).
MAO-B inhibitors (used in Parkinsons disease).
Non-selective MAO inhibitors
Non-selective MAOIs cause a rapid and
sustained increase in the CNS
concentration of NA, 5HT and dopamine.
They are very effective for the rapid
control of severe depression.
They are generally long lasting, due to the
irreversible inhibition of MAO.
They should not be given together with
tricyclic antidepressants or SSRIs.
Adverse effects of non-selective MAOIs
Adverse effects include:
Postural hypotension.
Atropine-like effects (antimuscarinic).
Weight gain.
Restlessness and insomnia.
Liver damage (rare, but MAOIs are avoided in
patients with abnormal LFTs).
In addition, non-selective MAOIs may cause severe
hypertension in the presence of tyramine-containing
foods. This is the cheese reaction.
The effect of tyramine on noradrenergic
transmission

1
-adrenoceptor
NA
Tyr
Uptake 1
Tyramine (from food) enters
peripheral adrenergic nerves via
the uptake 1 system. It is taken up
into vesicles, where it displaces NA
into the cytosol.

Cytosolic NA may then leak out of
the nerve via the uptake 1 system,
and activate post-synaptic
receptors.

Tyramine is normally destroyed by
MAO-A in the gut wall and liver.

NA
Tyramine
Uptake 1
The cheese reaction
Tyramine is a product of bacterial fermentation, and is
found in foods where such a reaction occurs (some beers
and wines, soft cheeses, and aged or cure meats, etc).
Tyramine is a substrate for both MAO-A and MAO-B, but as
tyramine does not cross the blood-brain barrier, its effects
are produced only by peripheral MAO-A.
Patients who ingest tyramine while taking non-selective
MAOIs, may develop life-threatening hypertension.
A dangerous hypertensive reaction can occur by a similar
mechanism in patients taking both non-selective MAOIs and
ephedrine or amphetamine.
Note: MAO-B inhibitors, which are used in Parkinsons
disease, do not produce a cheese reaction. They selectively
increase the neuronal dopamine concentration.
Non-selective MAOIs
Drugs in this class (irreversible non-selective
inhibitors of MAO) include:
Phenelzine
Tranylcypromine
Isocarboxazid
There is a reversible non-selective inhibitor of
MAO moclobemide.
Moclobemide appears to cause less severe cheese
reactions, but tyramine containing food is still best
avoided.
The less severe cheese reaction is probably related to
the less sustained inhibition of the enzyme.
Non-selective MAO Inhibitors
The use of these drugs is limited due to the
complicated dietary restrictions required of
patients taking MAOIs.
Non-selective MAOIs therapeutic
uses
Depressed patients who are
unresponsive or allergic to
TCAs or who experience
strong anxiety.
Low psychomotor activity
(have mild stimulant effect).
Phobic states.
Atypical depression: Labile
mood, rejection sensitivity,
and appetite disorders.
TCAs
Non-selective MAOIs
Antidepressant effects
required 2-4 weeks of
treatment.
The enzymatic
regeneration when is
irreversibly inactivate
occurs several weeks
after termination of
the drug.
2- 4 weeks
Non-selective MAOIs ADR
Severe and unpredictable effects.
Patients that ingest tyramine-contained foods,
causes the release of large amounts of
catecholamines (tachycardia, headache, nausea,
hypertension, cardiac arrhythmias and stroke)
because the tyramine normally is inactivated by
MAO in the gut. Phentolamine and prazosin are
helpful in the management of tyramine-induced
hypertension.
May be dangerous in severely depressed patients
with suicidal tendencies.
Drowsiness, orthostatic hypotension, blurred
vision, dry mouth, dysuria and constipation.
Should not be coadministered with SSRIs
(serotonin syndrome) (six weeks before).
SSRI MAOI
Atypical antidepressants
They are not more
efficacious than the
TCAs or SSRIs.
Bupropion
Mirtazapine
Nefazodone
Trazodone
Atypical antidepressants
Bupropion:
Extended release formulation.
Is unique in that it decreases the
craving for nicotine in tobacco
abusers.
ADR: Dry mouth, sweating,
tremor, and seizures at high
doses.
Atypical antidepressants
Mirtazapine:
Block 5-HT
2
and
2

receptors.
Antihistaminic activity
(sedative) may be
used in depressed
patients having
difficulty sleeping.
Increased appetite
and weight gain.
Atypical antidepressants
Nefazodone and trazodone:
Inhibitors of the serotonin reuptake, block the
5-HT
1
presynaptic autoreceptors and increase
serotonin release.
Block H
1
activity (sedating).
Cause priapism.
Other antidepressant drugs
Flupenthixol (a neuroleptic) has anti-depressant
effects, and is used in depression at low doses.
Reboxetine, a selective inhibitor on NA reuptake.
Tryptophan, the amino acid precursor of 5HT,
may be used as adjunctive therapy.
St Johns wort (a plant extract). It contains
hyperformin, a monoamine transport inhibitor. It
is a potent inducer of cytochrome P
450
, and will
interact with the metabolism of many other
drugs.
P450 interactions the critical list
The plasma concentration of many drugs may be
affected by drugs that induce or inhibit cytochrome P
450
.
Do not forget the following critical list is drugs whose
metabolism may be altered by P
450
inducers or inhibitors
Warfarin
Anticonvulsants (phenytoin, carbamazepine, others)
Anti-AIDS drugs
Protease inhibitors
Non-nucleoside RT inhibitors
Cyclosporine A
Oral contraceptives
Sedating, useful
for agitation
GI
distress
Orthostatic
hypotension
Weight
gain
SSRIs Citalopram - + - -
Escitalopram - + - -
Fluoxetine - + - -
Fluvoxamine + + - -
Paroxetine + + - -
Sertraline - + - -
SNRIs Venlafaxine - + - -
Duloxetine - + - -
Atypicalantidepressants Bupropion - - - -
Mirtazapine + - - +
Nefazodone + + - -
Trazodone + - - -
TCA Amitriptyline + - + +
Amoxapine + - - -
Clomipramine + + - +
Desipramine - - - -
Doxepin + - + +
Imipramine + - - +
Maprotiline + - - -
Nortriptyline + - - -
Potriptyline - - - -
Trimipramine + - - +
MAOI Phenelzine - - + -
Tranylcypromine - - + -