Drugs acting on CNS

ANTIDEPRESSANTS

Dr. Muhammad Sarfraz

College of Pharmacy Al-Ain University
Al Ain, UAE.
Depression

The symptoms of depression are intense feelings of

sadness, hopelessness, as well as the inability to
experience pleasure in usual activities, changes in
sleep patterns and appetite (poor), loss of energy,
and suicidal thoughts
Symptoms
Mania (mental illness) characterized by
opposite behavior that is enthusiasm, rapid
thought, speech patterns, extreme self
confidence, and impaired judgment.
There are three types of depression
I. Reactive (exogenous) depression
has a sudden onset and lasts for months and is
usually caused by an event such as the loss of a loved
one.
Treated by benzodiazepine
II. Major (unipolar)
characterized by losing interest in work and home
patient is unable to complete tasks and falls into a
deep depression
There are three types of depression
Causes include genetic predisposition, social
and environmental factors, and biologic
conditions.
Benzodiazepines are the drugs of choice
III.Bipolar affective (manic-depressive)
the patient undergoes moods swings from
manic (euphoric) to depressive (dysphoric).
Lithium is prescribed
 NEUROTRANSMITTER
ACTION

1. Neurotransmitter synthesis

2. Neurotransmitter storage

3. Vesicle transport
4. Vesicle fusion and Neuro-
transmitter release

5. Auto-receptor binding

6. Receptor binding

7. Neurotransmitter reuptake/
enzyme degradation
 Mode of action
All antidepressants function by increasing availability
of monoamines (5-HT, NA or DA) by one of the
following methods:
• Presynaptic inhibition of reuptake of 5-HT, NA or DA.
• Antagonist activity at presynaptic inhibitory 5HT or
NA receptors which enhances neurotransmitter
release.
• Inhibition of Monoaminase oxidase, reducing NT
breakdown.
• Increasing availability of NT precursors.
Initial resolution of depressive symptoms takes
minimum of 2-4 weeks.
Classification of Anti Depression
Drugs
• Selective serotonin reuptake inhibitors (SSRIs)

• Tricyclic antidepressants (TCAs)

• Serotonin-norepinephrine reuptake inhibitors

(SNRIs)

 Monoamine oxidase inhibitors (MAOIs)

▫ Irreversible
▫ Reversible
• Norepinephrine-dopamine reuptake inhibitors
(NDRIs)

• Serotonin antagonist and reuptake inhibitors

(SARIs)
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRIs)
• Citalopram: Major depression
• Escitalopram: Major depression and various other
anxiety disorders
• Fluxoetine: Major depression, OCD, bulimia, etc
• Fluvoxamine: (Obsessive Compulsive Disorder) OCD
• Paroxetine: Major depression or anxiety
• Sertraline: Major depression or anxiety
 MOA:
• Serotonin is a neurotransmitter, a brain messenger chemical that carries signals
between nerve cells in the brain and is thought to be involved in regulating many
functions, influencing emotions, mood, memory and sleep.

• Depression is associated with reduced levels of the monoamines in the brain, such
as serotonin (5-HT).

➢ The selective 5-HT re-uptake inhibitors (SSRIs) are thought to restore the
levels of 5-HT in the synaptic cleft by binding at the 5-HT re-uptake transporter
preventing the re-uptake and subsequent degradation of 5-HT.

• This re-uptake blockade leads to the accumulation of 5-HT in the synaptic cleft and
the concentration of 5-HT returns to within the normal range.

• This action of SSRIs is thought to contribute to the alleviation of the symptoms of

depression.
MOA:
• SSRIs do not have a significant affinity for histaminergic, alpha-1 adrenergic,
postsynaptic dopamine, GABA, or glutamate receptors nor do they inhibit
monoamine oxidase (MAO).
• 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 .

•Therapeutic uses:
•Depression, obsessive–compulsive disorder, generalized anxiety disorder,
posttraumatic stress disorder, social anxiety disorder, premenstrual
dysphoric disorder, and bulimia nervosa.
Some commonly observed adverse effects of selective
serotonin reuptake inhibitors.
Fluoxetine:
The most widely prescribed antidepressant since it
is as effective as TCAs, has fewer side effects, and is
less dangerous; but should be avoided taking with
MAOIs.
 Mechanism of action

Selective inhibition of serotonin reuptake to

intensify transmission at serotonergic synapses;
produces CNS excitation
 Therapeutic uses

primarily for depression, obsessive compulsive

disorder, bulimia nervosa (eating disorder)
 Fluoxetine:
 Pharmacokinetics
▫ well absorbed regardless of food; 94% protein bound;
fluoxetine (half-life 2 days) hepatic conversion to
norfluoxetine (half-life 7 days) then excreted in urine
and takes 4 weeks for steady state.
 Adverse effects
▫ the SSRIs are considered to have fewer and less severe
adverse effects than the tricyclic antidepressants and
monoamine oxidase inhibitors
▫ headache, sweating, anxiety and agitation, gastrointestinal
effects (nausea, vomiting, diarrhea), weakness and fatigue,
sexual dysfunction, changes in weight, sleep disturbances
(insomnia and somnolence)
 Serotonin syndrome
• All SSRIs have the potential to cause
serotonin syndrome, especially when
used in the presence of a MAOI or other
highly serotonergic drug.
• Serotonin syndrome may include the
symptoms of hyperthermia, muscle
rigidity, sweating, myoclonus (clonic
muscle twitching), and changes in
mental status and vital signs.
• Administration of 5-HT2A antagonists
(cyproheptadine) for treating
serotonin syndrome.
• Discontinuation syndrome,-headache,
malaise, and flu-like symptoms,
agitation, changes in sleep pattern.
 Tricyclic antidepressants (TCAs)
ON THE MARKET

• Amitriptyline
• Nortriptyline
• Protriptyline
• Imipramine
• Desipramine
• Doxepin
• Trimipramine
• Side effects have made them second line of defense to
SSRIs but they are good for treatment resistant
depression bc they are so strong.
Amitriptyline – most widely used, most effectve
Nortriptyline – same thing
Protriptyline – depression UNIQUE BECAUSE IT IS
ENERGIZING rather than sedating
Imipramine – used for major depression and
enuresis
Desipramine – active metabolite of imipramine, used
for neuropathic pain
Doxepin – used for depression and insomnia
Trimipramine – depression, insomnia, and pain
• MOA: They block the reuptake of serotonin and norepinephrine
in presynaptic terminals, which leads to increased concentration of
these neurotransmitters in the synaptic cleft.
• The increased concentrations of norepinephrine and serotonin in
the synapse likely contribute to its anti-depressive effect.
• Additionally, they act as competitive antagonists on post-
synaptic alpha cholinergic (alpha1 and alpha2), muscarinic,
and histaminergic receptors (H1). .
• However, actions at these receptors are likely responsible for many
of their adverse effects.
• .
Tricyclic antidepressants (TCAs)
 1/30/2024

Pharmacokinetics
 Long and variable half-lives; given in single daily dose
 Most tricyclics are incompletely absorbed and undergo
significant first-pass metabolism
 Highly protein bound and relatively high lipid solubility.
 The TCAs have a narrow therapeutic index
 Therapeutic Uses 1/30/2024

1. Depression—Takes 1–3 weeks for initial responses

2. chronic pain (neuropathic pain)
3. Bipolar disorder, chronic insomnia, attention-
deficit/hyperactivity disorders, and panic disorder
 Adverse Effects
Orthostatic hypotension is most common;
anticholinergic effects; sedation; cardiac toxicity is
most serious; seizures
weight gain commonly occur with TCAs.
Some commonly observed adverse effects
of tricyclic antidepressants.
TCAs interactions Potentiate effects of
biogenic amine drugs
by preventing their
Mutual enhancement: removal from the
Hypertension synaptic cleft.
Hyperpyrexia
Convulsions
Coma

MAOI Direct-acting
Adrenergic
drugs
TCA
Ethanol Indirect-acting
CNS depressants Adrenergic drugs

Block effects of
Toxic sedation indirect-acting
symphatomimetic
drugs.
SNRIs (Serotonin-norepinephrine reuptake
inhibitors ) on the market

• Venlafaxine

• Duloxetine

• Levomilnacipran

• Desvenlafaxine
•MOA- inhibition of presynaptic
neuronal uptake of 5-HT (serotonin)
and norepinephrine following
release from the synaptic cleft.
•Prevention of reuptake prolongs
the persistence of these
monoamines in the synaptic cleft
within the central nervous system
Proposed mechanism of action of
(CNS). selective serotonin-norepinephrine
reuptake inhibitor antidepressant drugs.
 SNRIs (Serotonin-norepinephrine reuptake inhibitors )
• Uses:
• Depression, anxiety ,Hot flashes and night sweats associated with
menopause, Peripheral neuropathy due to chemotherapy, Attention-
deficit/hyperactivity disorder (ADHD), Obsessive- compulsive disorder
(OCD), Migraine.
• May be effective in treating depression in patients in whom
SSRIs are ineffective
• Adverse effects: nausea, headache, sexual dysfunction, dizziness,
insomnia, sedation, and constipation.
• The SNRIs may precipitate a discontinuation syndrome if treatment is
abruptly stopped.
• Suicide risk.
 SNRIs (Serotonin-norepinephrine reuptake inhibitors )
•The SNRIs, unlike the TCAs, have little activity at α-adrenergic,
muscarinic, or histamine receptors and, thus, have fewer of
these receptor-mediated adverse effects than the TCAs.
•Their use is contraindicated in pregnancy.
•DRUG INTERACTIONS
•Monoamine oxidase inhibitors (MAOIs)
•Tricyclic antidepressants (TCAs)
•Anticoagulants
•Antihistamines
•Alcohol
•Ketoconazole
MAOIs (Monoamine oxidase
inhibitors) ON THE MARKET

• MAO Inhibitors (nonselective)

▫ Phenelzine
▫ Tranylcypromine
▫ Isocarboxazid

▫ MAO-B Inhibitors (selective for MAO-B)

▫ Selegiline Rasagiline
• MOA: The MAOIs may irreversibly or reversibly inactivate the
MAO enzyme, permitting neurotransmitters to escape
degradation and, therefore, to accumulate within the presynaptic
neuron and leak into the synaptic space This results in
increased stores of norepinephrine, serotonin, and dopamine
within the neuron and subsequent diffusion of excess
neurotransmitter into the synaptic space.
• MAOIs remain a useful and efficacious tool in treating atypical
depression, panic, social anxiety disorder, treatment-
resistant depression, and bipolar disorder.
• There are two main isoenzymes of monoamine oxidases:
MAO-A and MAO-B. Norepinephrine, epinephrine,
dopamine, tryptamine, and tyramine are all oxidized by
both isoenzymes.
• On the other hand, serotonin is mainly oxidized by MAO-A.
 1/30/2024

 are well absorbed after oral administration

 are metabolized in the liver, excreted mainly by the GI
tract
 Used as second- and third-choice drugs especially since
major problem is hypertensive crisis with tyramine foods.
 indicated for depressed patients who are unresponsive or
allergic to TCAs or who experience strong anxiety.
 also useful in the treatment of phobic states
 atypical depression, may respond to MAO inhibitors
 1/30/2024

 when switching to another antidepressant agents, a

minimum of 2 weeks of delay must be allowed after
termination of MAO inhibitor therapy
 Adverse effects : include drowsiness, orthostatic
hypotension, blurred vision, dry mouth, dysuria, and
constipation
▫ MAOI cause excessive central stimulation and weight
gain.
▫ Adverse reactions may be avoided by giving the drug in
small divided doses
 1/30/2024

 Certain foods can interact with MAOIs and produce

severe reactions.
▫ The most serious reactions involve tyramine -rich
foods, such as red wines, aged cheese
▫ Foods with moderate tyramine contents for
example, ripe banana may be eaten occasionally,
but with care
NOREPINEPHRINE-DOPAMINE
REUPTAKE INHIBITORS (NDRIS)
• Current drugs
▫ Bupropion
Mechanims of Action
▫ Similar to SSRIs and SNRIs
▫ More potent in inhibiting dopamine
▫ Also anα3-β4 nicotinic antagonist Bupropion 1:1
• Adverse effects
▫ Lowers seizure threshold
▫ Suicide
▫ Does not cause weight gain or sexual
dysfunction (even used to treat the two)
 (SARIs)
Serotonin antagonist and reuptake inhibitors
SARIs work by inhibiting serotonin reuptake in the brain. They act as antagonists to
inhibit a certain serotonin receptor—known as the 5HT2a receptor—and block
the function of the serotonin transporter protein, thereby increasing the amount of
active serotonin throughout the central nervous system (CNS).
Trazodone use also results in some histamine and adrenergic receptor blockade in
the brain; nefazodone additionally inhibits norepinephrine reuptake, though less
potently than its effects on the serotonergic system.4
,Mode: 5HT reuptake inhibitor & antagonist.
(sedation/ antihistamine)
Indication: Depression (+insomnia) / Anxiety
Advantage: Less antimuscranic/ cardiotoxic than TCA.

• Trazodone
• Nefazodone
 Mania & bipolar disorder
Mania: Mental disorder characterized by extreme self-confidence, elevated mood & impaired judgment.
Mood stabilizing drugs “Anti-manic drug”
Lithium - Carbamazepine - Valproate - Lamotrigine
Lithium carbonate
P/K • Monovalent cation that have some characteristics of sodium.
• Well-absorbed orally,
• Not bound to plasma protein & not metabolized in liver.
• Excreted in urine and (tears. saliva, sweat & milk).
MOA decreasing release of NE, dopamine and serotonin
Uses 1 Acute mania.
2 Prophylactic against recurrence of bipolar disorder.
3 Aggressive behavioral disorder.
4 Inappropriate ADH secretion.
SE 1 Hypothyroidism.
2 Nephrogenic diabetes insipidus.
3 Cardiac arrhythmias.
4 Weight gain.
Toxicity Plasma levels of 1.5-3 mmol/L: tremors, ataxia, drowsiness, thirst & diarrhea.
Plasma levels of 3-5 mmol/L: confusion convulsion, dehydration & coma.
ttt of 1 Gastric lavage
toxicity 2 Osmotic diuretic “mannitol” C#increase lithium excretion 3- Hemodialysis in severe cases
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Questions !