Anti Depressant Drugs are used to treat Depression. Depression is a disorder of mood and it is classified as an affective disorder. Anti Depressant Drugs are classified into two major types of depression: unipolar depression and bipolar depression. In this note, we will describe the Classification, Mechanism of Action, Adverse Effects, Therapeutic Uses, and Drug Interactions of Anti Depressants.
Depression is a disorder of mood and hence it is classified as an affective disorder. There are two major types of depression: unipolar depression and bipolar depression. Unipolar depression is further sub-divided into reactive depression and endogenous depression. About 80% of depressed patients experience unipolar depression in which the mood swings in one direction only i.e. either depression with a feeling of worthlessness or depression with irritability. About 60% of unipolar depressed patients show reactive depression manifested by feelings of sadness or grief and anxiety due to reasons like the death of a loved one, unemployment, physical illness, or social problems. It is self-limiting and responds to antianxiety drugs. About 25% of unipolar patients are having endogenous depression with suicidal thoughts. It is not self-limiting unless treated with an antidepressant drug or by electroconvulsive therapy (ECT). It results either due to genetic causes or due to disturbed neurotransmission of NE, 5-HT, or DA in certain areas of the brain.
Symptoms of Depression
Symptoms of Depression includes:
- Sleep disturbance
- Feeling of guilt
- Ugliness, and
- Loss of Libido
Classification of Anti Depressant Drugs
Classification of anti depressants on the basis of Mechanism of Action is given below:
- Tricyclic antidepressants (TCAs): These drugs block NE and 5-HT
- NA + 5-HT reuptake inhibitors: Imipramine, Clomipramine, Amitriptyline, Doxepin
- Predominantly NA reuptake inhibitors: Desipramine, Nortriptyline, Amoxapine, Reboxetine
- Selective serotonin reuptake inhibitors (SSRIs): Sertraline, Fluoxetine, Fluvoxamine, Paroxetine, Citalopram, Escitalopram
- Atypical antidepressants: Trazodone, Nefazodone, Bupropion, Mirtazapine, Mianserin
- Antidepressants of natural origin: St. John’s wort (Active principle: Hyperforin)
- MAO inhibitors:
- Non-selective: Tranylcypromine;
- Selective: Moclobemide
Mechanism of Action of Different Anti Depressant Drugs
Mechanism of Action of different types of Anti Depressants are discussed below:
- Drugs that block NE and 5-HT reuptake: These are tricyclic antidepressants. They block the reuptake of NE and 5-HT into their neuron by inhibiting respective transporters. It leads to more availability and a longer stay of NE and 5-HT at their respective receptor sites.
- SNRIs: Besides the effects shown by tricyclic antidepressants, SNRIs lack α1- adrenergic, histamine H1 and cholinergic receptor blocking properties of TCAs. Hence, they have fewer side effects.
- Drugs blocking NE reuptake: These drugs predominantly inhibit NE reuptake which results in increased concentration of NE in the synaptic cleft.
- SSRIs: They selectively increase levels of serotonin in the synaptic cleft. They are most commonly prescribed antidepressant drugs. All antidepressants described above exhibit a lag of 2-3 weeks to produce desirable clinical effects.
- Atypical antidepressants: Atypical antidepressants have different mechanisms of action. Trazodone/ Nefazodone inhibits the uptake of 5-HT, blocks the 5-HT2A receptor, and desensitizes the presynaptic 5-HT receptor. Mianserin blocks presynaptic α1-receptors and increases the release of NE in the brain. Mirtazapine acts by increasing both NE and 5-HT release. Bupropion is a weak inhibitor of neuronal reuptake of 5-HT, NE, and DA.
- Antidepressants of Natural Origin: Active ingredients of St. John’s wort (Hypericum perforatum) are monoamine reuptake inhibitors, mild MAO inhibitors, and stimulants at GABA receptors.
- MAO Inhibitors: MAO inhibitors increase brain amine levels by inhibiting their metabolism, resulting in the increase of NE and 5-HT. There are two isoforms of MAO: MAO-A and MAO-B.MAO inhibitors need a biological lag of 2-3 weeks to exert clinical effects.
Pharmacokinetics of Anti Depressant Drugs
Oral absorption of most antidepressant drugs is good; still, the bioavailability is uncertain because of their first-pass metabolism. Bioavailability of Citalopram and Protryptyline is90%. The plasma half-life of most antidepressants is long, hence plasma concentration is built up slowly. After reaching steady-state, one daily dose at bedtime is enough. Plasma half-life for some antidepressants is low. Amoxapine (8 hours), Nefazodone (2-4 hours), Trazodone (4-8 hours), and Venlafaxine (4-9 hours) are some examples. The half-life is longer due to their metabolites except for Fluvoxamine, Paroxetine, and Protriptyline. Among MAO inhibitors, Moclobemide is readily absorbed but its first-pass metabolism reduces
bioavailability; its half-life is 1-3 hours.
Therapeutic Uses of Anti Depressant Drugs
Therapeutics uses of different anti depressants are given below:
- Nocturnal Enuresis: It is the condition of bed wetting which occurs to the children of ages of 2-3 year due to inadequate control over bladder. The treatment involves bladder training and correction of psycho pathological factors.
- Bulimia Nervosa: It is a behavioral disorder in which the patient over eats then vomits or fasts to undo the threat of weight gain.
- Other Uses: Tricyclic Antidepressants are also used in Migraine. They are also widely used in panic disorder, and for relieve from headache.
- MAO inhibitors are widely used in the treatment of endogenous unipolar depression. They are also used in panic disorder, bulimia nervosa, and post traumatic reaction. They are also used as a second line when TCAs are fail to work. The Selective MAO B inhibitor selegiline is used significantly for treating Parkinsonism.
- SSRIs like Fluoxamine and Fluoxetine are useful in treating bulimia nervosa.
- SSRIs like Paroxetine or reversible MAO-A inhibitor Moclobemide are preferred for school phobia and social phobia. Paroxetine with Alprazolam are preferred for posttraumatic stress disorder. SSRIs are helpful in controlling impulse control disorder like gambling.
- Bupropion is used to treat nicotine dependence and smoking caessation.
- Citalopram is used to treat ethanol abuse syndrome.
Adverse Effects of Anti Depressant Drugs
Adverse effects are dependent on the type of anti-depressant based on its mechanism
- TCAs which block uptake of NE or NE + 5-HT: TCAs with histamine H1 receptor blocking actions (Amitriptyline, Doxepin and Trimipramine) cause more sedation. Drugs like Maprotiline, Bupropion and Clomipramine lower seizure threshold and precipitate epileptic seizures. Drug like Amoxapine can induce extrapyarmidal effects, gynacomastia (in males) and galactorrhoea (in females).
- SNRIs: These drugs have serotonergic side effects like discontinuation syndrome.
- SSRIs: Some patients complain of agitation, anxiety and insomnia. Few others complain of sexual dysfunction including decreased libido and delayed ejaculaton. Nausea and loose stools are also experienced by few patients. Sudden withdrawal causes discontinuation syndrome leading to dizziness, paresthesias and headache.
- MAO Inhibitors: Their adverse effects include postural hypotension (in elders), weight gain, dizziness and sexual dysfunction.
- Atypical Antidepressants: Trazodone causes nausea, sedation, postural hypotension and priapism leading to impotence. Bupropion causes agitation and insomnia. Mirtazapine and Mianserin cause sedation due to histamine H1-blockade. Hepatotoxicity and blood dyscrasias have also been reported.
Drug Interection of Anti Depressant Drugs
They are classified under three categories:
- Interactions with TCAs and related Drugs
- TCAs potentiate effects of directly acting sympathomimetics causing rise in BP and arrhythmias; but inhibit effects of indirectly acting sympathomimetics.
- Anticholinergic drugs aggravate toxicity of TCAs.
- Phenytoin, Chlorpromazine and Aspirine displace TCAs from their protein binding sites leading to increased effect of TCAs.
- MAO inhibitors have synergistic action with TCAs causing hypertension, arrhythmiasand seizures.
- Interactions with MAO inhibitors
- Food articles containing tyramine, like cheese, beer, red wine, banana, yoghurt and pickled meat when used with MAO inhibitors can cause hypertensive crisis.
- MAO inhibitors with TCAs or with directly/indirectly acting sympathomimetics can cause hypertension, arrhythmias and seizures.
- MAO inhibitors inhibit degradation of DA. This can result in hypertension.
- MAO inhibitors retard metabolism of drugs like morphine causing severe respiratory depression. It also retards metabolism of sulfonylureas causing hypoglycaemia and that of chloroquinine causing toxicity of chloroquine.
- Interactions with SSRIs
- SSRIs inhibit metabolising enzymes like CYP2D6 and CYP3A4. As a result, plasma levels and toxicity of TCAs, Haloperidol, Clozapine, Warfarin, Dextromethorphan, Terfenadine, Astemizole and Cisapride are increased. Elevated levels of Terfenadine, Astemizole and Cisapride can precipitate arrhythmias.
- SSRIs with MAO inhibitors result in elevated levels of 5-HT causing “serotonin syndrome” leading to hyperthermia, muscle rigidity, tremors and rapid changes in mental status along wirth cardiovascular collapse.
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