medicine relared

1. ANTIDEPRESSANTS
DR S B M.

2. DEPRESSION
• Affective disorder with pathological changes in
Mood (not thought process).
• UNIPOLAR – 80% cases;
About 25% of U depressed patients are
endogenously depressed with suicidal thoughts.
This can occur at any age , not self limiting; needs
treatment with antidepressants or ECT.
• BIPOLAR or Manic Depressive Psychosis- 20%;
cyclic manifestations of depression followed by
mania.

3. MECHANISM OF DEPRESSION.
• Depression is caused by functional deficit of NE and/or 5HT or of
DA at certain sites of brain. Mania results from excess of these
neurotransmitters.
Evidences- 1. NE & 5HT uptake inhibiting or MAO- A inhibiting drugs
facilitates NE/5HT neurotransmission and acts as effective
antidepressant drugs.
2. CSF levels of 5HIAA, a metabolite of 5HT and urinary levels of
MHPG, a metabolite of NE, are found to be low in Depression.
But there are inconsistencies in the monoamine hypothesis—
1. Although antidepressant drugs produce blockade of NE/5HT
within hours, their clinical benefits typically appear after several
weeks of treatment.
2. Some clinically effective antidepressant drugs have atypical
actions and lack any NE/5HT uptake inhibiting action.

4. MECHANISM OF DEPRESSION
• A most consistent adaptive change seen with
different kinds of antidepressants drugs is the
downregulation of beta1, beta2, alpha2
adrenoreceptors as well as 5HT2 receptors. ECT
also brings about a downregulation of beta1 &
beta2 receptors.
• Evidence shows that in depression there is
significant drop in BDNF( Brain-derived-
neurotropic -factor). Administration of
antidepressant increases BDNF levels.

5. TCAs ( TRICYCLIC ANTIDEPRESSANTS)
• First gen antidepressants- early developed compound – in addition to
uptake blockade, these have direct effects on adrenergic, cholinergic &
histaminergic receptors.
• Second generation antidepressants- selective action on amine uptake;
SSRIs or SNRIs with no direct action on
cholinergic/adrenergic/histaminergic receptors or have some atypical
features.
Limited spectrum of action resulting in fewer side effects.
Most prominent action of TCAs is their ability to inhibit
NET(Norepinephrine Transporter) &SERT( Serotonin Transporter) located
at neuronal & platelet membrane. Thus, the availability of NA & 5HT in
synaptic cleft is increased.
Inhibition of DA uptake correlates with stimulant action. Amphetamines
& Cocaine which are CNS stimulants – are strong inhibitors of DA uptake.
Imipramine is the prototype.

6. ACTIONS OF IMIPRAMINE( TCA)
• 1. CNS- Sedation initially; after 3 weeks mood is gradually
elevated, patient becomes more communicative & takes
interest in self & surroundings. They lower seizure
threshold & produce convulsion in overdose.
• 2. ANS- TCAs are potent anticholinergics – dry mouth,
blurring of vision, constipation, urinary hesitency.
• 3 CVS- Tachycardia, arrhythmias, postural hypotension.
Tolerance to anticholinergic & hypotensive effects develop
gradually but antidepressant action is sustained. When
high doses are used for long periods, physical dependence
occurs. Gradual withdrawl is recommended.

7. PK OF TCAs
• Extensively metabolized in liver.
• Because of relatively long T1/2, once daily dosing
at bedtime is usually practiced.
• Unusual THERAPEUTIC WINDOW phenomenon is
observed ( optimal antidepressant is exerted at a
narrow band of plasma conc ( 50-200ng/ml)
• Dose needs to be individualized & titrated with
response but plasma conc are not a reliable guide
for adjusting the dose of TCAs.

8. ADVERSE EFFECTS OF TCAs
• Side effects are common – so SSRIs, SNRIs & atypical
antidepressants have become the first line of drugs.
• Anticholinergic effects.
• Sedation, mental confusion, weakness.
• Increased appetite & weight gain.
• Some may switch to dysphoric-agitated state or to mania.
(probably Bipolar cases- the other pole being unmasked by
antidepressants)
• Sweating & fine tremors.
• Sz threshold is lowered- precipitation of fits.
• Postural hypotension, specially in elderly.
• Cardiac arrthhymia.
• Sexual dysfunction.

9. DRUG INTERACTION
• 1. TCAs potentiate directly acting
sympathomimetic amines.
• 2.Potentiates CNS depressants, including alcohol
& antihistaminics.
• 3. SSRIs inhibit metabolism of several drugs
including TCAs – dangerous toxicity can occur if
both are given together.
• TCAs with MAO inhibitors- dangerous
hypertensive crisis with excitement &
hallucinations can occur.

10. SELECTIVE SEROTININ REUPTAKE
INHIBITORS (SSRIs)
• Efficacy of 2nd gen antidepressants is higher than older TCAs & RIMAs.
• Improved tolerability at therapeutic doses as well as safety in overdose.
• Extensive use in anxiety, phobias, panic, ocd.
• Produce little or no sedation, do not interfere with cognitive &
psychomotor function or produce anticholinergic side effect.
• No alpha adrenergic blocking action- no postural hypotension- suitable for
elderly.
• Prominent GI side effects- nausea, loose motion.
• SEROTONIN SYNDROME- agitation, rigidity, hyperthermia, delerium,
sweating, twitching followed by convulsions can be ppt when any
serotonergic drug ( MAO I, Tramadol, Pethidine) is taken by a patient
receiving SSRIs.
• Because of freedom from psychomotor & cognitive impairment, SSRIs are
preferred over TCAs for prophylaxis of recurrent depression ( in
combination with Lithium/Valproate)

11. SSRIs
• FLUOXETINE- 1st SSRI, bicyclic compound, slower onset, longest
acting. Approved for use in children 7 years or older for depression
& OCD. Agitation & dermatological reactions are frequent.
• FLUVOXAMINE- shorter acting, specifically recommended for
generalized anxiety disorder & OCD.
• SERTRALINE- juvenile depression, anxiety & post traumatic stress
disorder.
• CITALOPRAM- Low drug interaction; preferred for mood disorders
in premenstrual dysphoric disorder.
• DAPOXETINE- for delaying premature ejaculation, taken 1 hr before
intercourse ( along with behavioral therapy)
• SSRIs are 1st choice drug for OCD, Panic disorder, social phobia,
eating disorder, PMDD, PTSD. Also used for anxiety disorder,
compulsive buying, kleptomaniac, mood elevation etc.

12. SNRIs (SEROTONIN &
NORADRENALINE REUPTAKE
INHIBITOR)
• VENLAFAXINE- may work in some resistant cases;
faster onset; mood changes & hot flushes in
menopausal symptoms, social anxiety & eating
disorders are benefitted. Safe in overdose.
• DULOXETINE- newer SNRI ; mildly sedating; less
side effects. Primarily indicated in diabetic &
other type of neuropathic pain, fibromyalgia,
stress urinary incontinence in females,
maintenance therapy in panic disorders.

13. ATYPICAL ANTIDEPRESSANTS
• MIRTAZEPINE- Blocks alpha2 auto/hetero receptors
enhancing both NA & 5HT release.
It is a H1 blocker & mod strong sedative suitable for
insomnia. Weight gain.
• BUPROPION- Inhibitor of DA & NA uptake has excitant
rather than sedative property.
A sustained-release formulation is used as an aid to smoking
cessation( better result with nicotine patch)
Infrequently used to treat depression with atypical features
or added to SSRI as an augmenting drug.
Dose of 150mg BD should not be exceeded as it lowers
seizure threshold.

14. USES OF ANTIDEPRESSANT DRUGS
• 1.ENDOGENOUS (MAJOR) DEPRESSION.
The less toxic, higher efficacy & more patient friendly
SSRI/SNRI/atypical antidepressants are now more prescribed.
Choice of particular drug depends on the secondary properties
(sedative, anticholinergic, hypotensive, cardiotoxic, seizure
precipitating)
Only antidepressants effective in juvenile depression are Fluoxetine
& Sertraline.
In patients not responding to initially selected drug, another atypical
antidepressant like Bupropion or valproate/Lithium is added.
Adding a 2nd gen antipsychotic drug in refractory cases is another
option.
After control, maintainence doses for months is recommended to
prevent relapse. Discontinuation may be attempted after 6-12
months. ECT may be given in severely depressed.

15. USES OF ANTIDEPRESSANT DRUGS
• 2. OCD- SSRIs, particularly FLUVOXAMINE is DOC. TCAs( sp
clomipramine) is also highly effective. SSRIs & TCAs also
reduce compulsive eating in BULIMIA & also in patients
with compulsive buying & Kleptomania.
• 3. Anxiety disorder- SSRIs & SNRIs exert a beneficial effect
in patients of social anxiety, generalized anxiety disorder,
Phobic disorders, Panic attacks & PTSD.
• 4. Neuropathic pain- Amitriptyline & other TCAs afford
relief in Diabetic & other type of Chronic pain ( post
herpetic neuralgia).
DULOXETINE- first line drug in diabetic neuropathy,
Fibromyalgia.
Pregabaline & Gabapentine are useful in neuropathic pain.

16. USES OF ANTIDEPRESSANT DRUGS
• 5. ADHD in children- TCAs with less depressant property
like imipramine, Nortryptiline, Amoxapine are first line
drugs.
• 6. Premature ejaculation- primary treatment is counselling
& behavioral therapy. DAPOXETINE is SSRI specially
introduced for this purpose; acts rapidly; 60mg taken 1 hr
before intercourse. CLOMIPRAMINE 10-25 mg TDS to be
taken regularly for max benefit.
• 7 Smoking cessation– Bupropion. ( with nicotine gum)
• 8.Enuresis– children above 5 yrs, IMIPRAMINE 25 mg at
bedtime is effective.
• Migraine– Amitriptyline.
• Pruritis – topical DOXEPIN used to relieve itching.

17. •THANK YOU