Antidepressants

Depression is a psychiatric illness characterized by mental and physical

symptoms, include depress mode , loss of interest in normal activities,
feeling of guilt, inability to take decisions, loss of confidence loss of
appetite , difficulty in sleep and suicide ideas.
• Amine theory: Depression occurs due to disturbances in the
catecholamines concentrations in the brain including the reduction in
serotonin, and noradrenaline in certain sites in the brain. In support
of this theory is the fact that most antidepressant drugs acts mainly
by increasing catacholamines centrally in the brain and reserpine a
drug which deplete catecholamines centrally in the brain can cause
depression as a side effect.
• However depression may be caused by more complex mechanisms
include genetic factors
 Drugs useful in the treatment of depression:
1. Tricyclic antidepressants: imipramine, amitriptyline, clomipramine.
2. Second generation: mianserine, maprotiline, amoxapen , trazodone,
bupropion, nefazodone and venlafaxine
3. Monoamine-oxidase inhibitors:
a. non-selective and irreversible: phenelzine, isocarboxizid,
tranylcypromine
b. selective and reversible (MAOI-A): meclobemide
4. Selective Serotonin reuptake inhibitors: Fluoxetine, ciotalopram,
paroxetine, Sertraline
5. Lithium : useful in manic-depression
Tricyclic-antideprssants:

Imipramine, amitriptyline, nortriptyline and clomipramine Called

tricyclic due to their chemical structure which contain three cycles
Mechanism of action: all acts by inhibiting the neuronal reuptake of
catechol-amine (noradrenaline and/ or serotonin) centrally in the brain
and increasing the brain stores of these amines.
They usually take two weeks for the full clinical benefit to occur.
Amitriptyline has a sedative effect in addition to the anti-depressant
action, so it is useful in agitated Patients. imipramine has less sedative
effect.
• Pharmacokinetics:
• Intestinal absorption slow and incomplete specially in high doses due
to anticholinergic effect
• Highly lipid soluble
• Extensive first pass metabolism
• Active metabolites
• High protein binding (85-90%)
Clinical uses:

1. Depression
2. Panic attacks and severe anxiety states
3. Nocturnal enuresis in children, due to anticholinergic effect and
changing sleep pattern
4. Co-analgesics: administered with analgesic drugs specially in
chronic pain as it improve pain control by inhibiting pain pathway
and relieving associated depression
Adverse effects:

1. anticholinergic: dry mouth, constipation, tachycardia, retention of

urine
2. CNS: tremor, sedation, confusion, insomnia, convulsions
3. Cardiovascular : postural hypotension(alpha blockade) , tachycardia,
ECG changes ( flat T wave, ST depression and QT prolongation) AV
block
4. Allergic reactions; skin rash, cholestatic jaundice and bone marrow
depression
Drug interactions with tricyclic antidepressants

1. Potentiates other CNS depressants as benzodiazepines and

barbiturates
2. Potentiate the effects of monoamine oxidase inhibitors
3. Potentiates the effect of Antimuscarnic drugs
4. Reduce the antihypertensive effect of guanithidine and clonidine by
inhibiting their neuronal uptake
5. Potentiate the effects of sympathomimetic amines as noradrenaline
and amphetamine
2. Second generation antidepressants:
• Trazodone:
Acts by antagonism at serotonin receptors (5HT-2A or 5HT2C) and blocking
presynaptic (alpha2) adrenoceptors and increase catecholamines secretion.
It lacks anticholinergic effects and cause less interactions with drugs and
relatively safe in overdose. But it may cause seizures especially in overdose
• Maprotiline:
Is a tetracyclic compound similar in action to the tricyclic compounds, has a
long half life and can be given in a single daily dose.
• Amoxapen:
Causes less cardiac toxicity but may cause extra-pyramidal symptoms
• Nefazodone
Also lacks anticholinergic effects, but may cause hypotension, it improve
sleep.
3.Monoamine oxidase inhibitors:

Irreversible and non-selective: phenelzine, isocarboxizide, trranylcypromine

They acts by irrevbersibly inhibiting the MAO enzymes and increase
catecholamines centrally in the brain, some of them has prolonged action even
after cessation of therapy. They are used only when there is no response to other
drugs. Also they take 2 weeks for clinical response to occur.

Adverse effects:
1. Atropine like action as dry mouth, blurring of vision, retention of urine and
constipation
2. CNS : anxiety, acute confusion, tremor, hyperreflexia.
3. Others, hepatocellular necrosis, skin rash and jaundice
Drug interactions:

1. Causes severe hypertension when given in combination with amines as

adrenaline ephedrine and amphetamine. This may lead to sub-arachnoid
hemorrhage
2. Also hypertensive reaction may occur following the ingestion of tyramine
containing food as cheese and banana
3. MAOIs can also inhibit the metabolism of other drugs as barbiturates and
hypoglycemic agents
 Reversible selective MAOIs (MAOI-A)

• Meclobemide:
• Inhibits MAO-A in the brain, but has no effect on MAO-B which is widely
distributed in the body including the GIT. Therefore meclobemide is less
likely to cause hypertensive reactions. It also has reversible action with loss
of all the activity after 24 to 48 hours following cessation of treatment.
Adverse effects:
• Nausea, vomiting, dizziness insomnia and agitation
• Less interaction with food and less toxicity in overdose
3. Selective serotonin reuptake inhibitors (SSRIs):
Fluoxetine, paroxetine, sertraline
Selectively inhibits serotonin uptake they have little effect on other
catechalamines dopamine and noradrenaline. They also not have effects on
muscarinic adrenergic or histamine receptors.
They have fewer incidences of adverse effects and can be given in a single
daily dose due to long half life
Adverse effects:
1. Nausea, vomiting and diarrhea
2. Headache, nervousness, agitation and insomnia
3. Fewer interactions with other drugs and free from cardiovascular side
effects
Lithium
Used clinically as lithium salts like lithium carbonate. Lithium is effective in the
treatment of manic-depression.
The mechanism of action include ; as a mono-valent cation LI + can replace Na+
ions which lead to altered neuronal function, it also interacts with second
messengers (G-proteins) and cause inhibition of inositol phosphate
Pharmacokinetics:
Lithium salts as lithium carbonate converted inside the body into lithium ions (Li+3)
Not bound to plasma proteins
Low therapeutic index so require serum level monitoring during treatment
Diuretics reduce renal clearance
Adverse effects:
1. CNS: drowsiness, dizziness, ataxia, tremor, dysarthria coma and convulsions
2. Cardiovasccular: hypotension and cardiac dysrhythmias
3. Nephrogenic diabetes insipidus( antagonize ADH hormone)
4. GIT: nausea, vomiting and diarrhea
Electroconvulsive therapy (ECT)

• Passage of electric charge across the brain by electrodes applied to the

scalp
• Useful in depression when drug treatment is not effective or when rapid
response is required as in suicidal patients or when patient stop eating or
drinking
• Probably act by releasing catecholamines in the brain
Anti Parkinson
 Parkinson disease
Parkinson disease (PD) is a chronic, progressive movement disorder
resulting from loss of dopamine in the brain, and is characterized by
rigidity, bradykinesia, postural disturbances, and tremor.
The name comes from when first described by London physicians
James Parkinson in 1817.
The age at onset of PD is variable, usually between 50 and 80 years,
with a mean onset of 55 years.
Drugs useful in Parkinson’s disease:
1. Levodopa(L-dopa)
2. Levodopa + a peripheral dopa decarboxylase inhibitor As carpidopa
and benserazide
3. Dopamine receptor agonist as ergot derivative bromocriptine,
pergolide,and non ergot dervitative ropinirole, prampixole
4. Stimulant of dopamine release as Amantadine
5. Monoamine oxidize inhibitors (MAO-B) as Selegiline
6. Catechol-o-methyl transferees inhibitor as tolcapone and entacapone
7. Centrally acting anticholinergic drugs as benzhexol, orphenadrine and
trihexyphenidyl
Levodopa
Used in the treatment of Parkinson disease because dopamine can not pass
the blood brain barriers, while L-dopa can penetrate the brain and
decarboxylated into dopamine.
L-dopa, the most effective drug available, is the immediate precursor of
dopamine. Ultimately, all PD patients will require L-dopa.

Pharmacokinetics:
rapidly absorbed with half-life of 1-2 hours, food delay the absorption
undergoes extensive peripheral metabolism with only small amount reach
the brain (low bioavailability)
The immediate response to levodopa is often dramatic, but the long-term
use is limited by the development of motor fluctuations. The most common
of these is the wearing-off effect.
Adverse effects of L-dopa:
1- GI disturbances; anorexia, nausea and vomiting, probably due to
stimulation of emetic centers in the brain can be reduce by slow dose
increment.
2- Cardiovascular; tachycardia, atrial fibrillation and ventricular extra
systoles (converted in the peripheral tissue into epinephrine).
3- CNS; abnormal movements (dyskinesia) as chorea, athetosis and
dystonia
4- Behavioral effects ; anxiety, depression, agitation, insomnia delusions,
hallucinations, nightmares and mood changes
5- Others: anticholinergic effects and fluctuation in response
B-Dopamine Agonists

1- The ergot derivative bromocriptine and the non ergots pramipexole ,

rotigotine , and ropinirole are beneficial adjuncts in patients with limited clinical
response to L-dopa.
2-The nonergots are safer and are effective as monotherapy in mild-
moderate PD as well as adjuncts to L-dopa.

A-In younger patients (e.g., age <65 years) with milder disease, the initiation of
a dopamine agonist is preferred.
B- In older patients (e.g.,age >65 years) with PD, it may be more appropriate to
initiate treatment with levodopa instead of a dopamine agonist
Bromocriptine:
• Is an agonist at dopamine D2- receptors. Usually given to patients not
responding to L-dopa, the combination of the two drugs together
allows the reduction of doses of both.
• Bromocriptine, pergolide, pramipixole and ropinirole are all effective
in patients with advanced Parkinson disease and they have duration
of action longer than levodopa
Adverse effects:
• Anorexia, nausea, vomiting and constipation
• cardiovascular: postural hypotension and cardiac dysrrhythmias
• Abnormal movements and mental disturbances
C-Catechol-O-Methyltransferase (COMT) Inhibitors

1-Tolcapone and entacapone are used only in conjunction with

carbidopa/L-dopa to prevent the peripheral conversion of L-dopa to
dopamine.
Tolcapone
Selectively and reversibly inhibits COMT enzyme can be given orally
useful in combination with L-dopa
Adverse effects:
Diarrhea, postural hypotension, dyskinesia and hallucination.
Hepatitis and hepatic failure.
 D-Monoamine Oxidase Type-B (MAO-B) Inhibitors
1-Inhibition of MAO-B is associated with reduced synaptic degradation of
dopamine and prolonged dopaminergic activity. Two selective MAOB
inhibitors, rasagiline and selegiline, are available for management of PD.

2-Selegiline is a first-generation MAO-B inhibitor that blocks dopamine

breakdown and can extend the duration of action of L-dopa (up to 1 hour) .
Selegiline is metabolized to the amphetamine derivatives , which have been
implicated in producing side effects such as insomnia and vivid dreaming.
3-Rasagiline is a second-generation selective inhibitor of MAO-B. It is
indicated as monotherapy in early disease or as adjunct therapy to
levodopa in advanced disease.
A-Rasagiline is differentiated from selegiline primarily in that it is a
more potent inhibitor of MAO-B, and it is not metabolized into
amphetamine-based metabolites.
E-Anticholinergic Medications
1-Anticholinergics (e.g. procyclidine, and trihexyphenidyl (benzhexol))
are more helpful in alleviating tremor and rigidity than bradykinesia
(rarely show substantial benefit for bradykinesia) . However, they are
poorly tolerated by elderly patients owing to their cognitive side
effects.
2-Their use is mostly restricted to patients with tremor that is not
respond to levodopa treatment.
• are useful in drugs induce Parkinson’s disease
• can be given alone in the early stage of Parkinson’s disease
• can also be combined with L-dopa
Amantadine
Increase the release of dopamine, can be given orally, less potent than
l-dopa, effective for short period of time.
It has antiviral activity against influenza type A
Adverse effect
nervousness, depression, irritability, hallucination and confusion
F-Amantadine

Amantadine reduces all the symptoms of parkinsonian, usually within

days after starting therapy; however, long-term use is limited in many
patients by the development of tachyphylaxis within 1 to 3 months.

2-Amantadine has been found to have antidyskinesia effects, the

finding has shifted its use from use as monotherapy in early disease to
that of an adjunctive agent in managing levodopa-induced
dyskinesias.