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Depression Monoamines in depression Serotonin Noradrenaline Dopamine Antidepressants, I Tricyclic antidepressants (TCA) Selective serotonin reuptake inhibitors (SSRI

) Monoamine oxidase inhibitors (MAOI) Noradrenaline and dopamine reuptake inhibitors (NDRI) Selective noradrenaline uptake inhibitors (SNRI) Antidepressants, II Serotonin and noradrenergic reuptake inhibitors (SSNRI) Noradrenaline and specific serotoninergic antidepressant (NaSSA) Serotonin 2A antagonist/reuptake inhibitor (SARI)

to the limbic system for anxiety. . obsession. anxiety. hypothalamus for appetite. agitation. Serotonin is synthesized from tryptophan: Serotoninergic neurons are concentrated in the Raphe nucleus in the brainstem. food craving and bulimia. It projects to frontal lobe. working memory. Noradrenaline Deficiency causes impaired attention. Serotoninergic neuron also exist in the gut. mediating mood and attention. projection to basal ganglia mediates akathisia. It projects to frontal cortex for mediation of mood. Noradrenaline is synthesized from tyrosine: Noradrenaline neuron are concentrated in an area called ‘locus coeruleus’. sleep centers for insomnia spinal cord for sexual function and vomiting center for nausea and vomiting. when overstimulated causes GI cramps and diarrhea. to limbic system mediating energy/fatigue and psychomotor agitation/retardation. slowness of information processing.Monoamine in depression Serotonin Deficiency causes depressed mood. depressed mood. compulsion. psychomotor retardation and fatigue. obsession and compulsions. problem with concentration. anxiety. panic. brainstem (blood pressure) and works on heart and bladder (tachycardia and urinary retention). to cerebellum mediating motor movements (tremor). phobia.

Dopamine There are four pathways in the brain using dopamine as the major neurotransmitter: - Mesocortical (cognition. D2 receptor is stimulated by dopaminergic agonist for the treatment of Parkinson’s disease and blocked by dopamine antagonist neuroleptics and atypical antipsychotics for treatment of schizophrenia. from D1-D5. . negative sx in schizophrenia) – ventral tegmentum  cortex Mesolimbic (positive symptoms in schizophrenia) – ventral tegmentum  nucleus accumbens Nigrostriatal (EPS in patients treated with antipsychotics) – substantia nigra  striatum Tuberoinfundibular (prolactin production) – arcuate nucleus  hypothalamus Dopamine is synthesized in the same pathway as noradrenaline: There are 5 receptors for dopamine.

Clomipramine. Discontinuation syndrome occur when tricyclic is withdrawn. Tricyclic antidepressants can also cause delirium. Barbiturates induces P450 2D6 so decreases serum levels of TCA by induction of enzymes. Nortriptyline Pharmacokinetics All tricyclics are rapidly absorbed and widely distributed. Alpha-1 blockade would lead to postural hypotension and sedation. The later two action (muscarinic blocking and alpha-1 adrenergic blocking effect) are responsible for most of the side effects of the medication. Note that all tricyclic antidepressants are class I antiarrhythmic and can lead to heart block (complete heart block. (antidepressant and anxiolytic functions). TCA thus potentiate warfarin action. anxiety disorders and eating disorders. secondary TCAs to a moderate extent and other antidepressants (bupropion. Tertiary TCAs inhibit P450 1A2 and most tricyclics inhibit P450 3A4. Note that by blockade of serotonin reuptake weight gain occur as a result of stimulation of 5HT-2 receptors. paroxetine and fluoxetine (SSRIs) potently. (See SSRIs) Drug interactions All tricyclics are metabolized by the enzyme system P450 2D6. nefazodone and other SSRIs). Muscarinic blockade would result in symptoms such as dry mouth. Secondary TCAs are inhibitors of P450 2D6. . venlafaxine. P450 2D6 is inhibited by cimetidine (histamine H2 receptor antagonist). SSRIs and L-tryptophan. these increases TCA serum levels. urinary retention. problem with visual accommodation as well as glaucoma. The second action – by blocking histamine H1 receptor. movement disorder and convulsion as their neurotoxic effect. this leads to anxiolytic action. sedation. constipation. TCAs can be used to beneficial effect with lithium.Tricyclic antidepressants Amitriptyline. The half-life of TCAs (or their active metabolite) is in the order of 24-36 hours. There are genetic variation in liver metabolism – one in 20 caucasian has problem with P450 2D6 which make them poor metabolisers of TCAs. Actions Most tricyclic antidepressants have FIVE different actions :- - Serotonin reuptake inhibitor (more potent with tertiary amine) Noradrenergic reuptake inhibitor (more potent with secondary amine) Histamine H1 blocker Muscarinic blocker Alpha-1 adrengic blocker Note that the initial two effects are responsible for the beneficial effect on depression. etc. They are thus contraindicated in heart block as well as recurrent myocardial infarction. weight gain (improved appetite – put it in the other way) and drowsiness can be useful or bad depending on situations.) as well as prolongation of QT interval. Imipramine.

Selective serotonin reuptake inhibitors Fluoxetine (Prozac®). Myoclonic jerks and Pyrexia. In this case drug should be stopped. interacts with antipsychotics. Instability of autonomic system. Serotonin syndrome is an acute toxic syndrome due to increased 5-HT activity. dopamine reuptake inhibitor (sertraline) Noradrenergic reuptake inhibitor. class Ic antiarrhythmics and beta blockers. Dreams. Manic chimps with GI discomfort – Confusion. Fluoxetine has the longest halflife (200 hours for its active metabolite) whereas drugs such as fluvoxamine has half life of 15 hours. John’s Wort. Somatic symptoms. .e. tricyclic antidepressants. 2D6 inhibitor (paroxetine) Sigma action. Sensory abnormality and Schizophrenia (for psychotic symptoms) Drug interactions SSRIs interact with MAOIs and St. Sweating SSRI discontinuation syndrome is characterized by sensory abnormality. disequilibrium. Depression. downregulation) which lead to both increase in serotonin secretion by the neuron as well as reduction of side effects as the drug is used for some time. characterized by confusion. nitric oxide synthase inhibitor. opiates. Sedation and dizziness occasional occurs. sweating and autonomic instability. insomnia and sexual dysfunction. Fluvoxamine interacts with P450 1A2 – interacts with caffeine. Fluvoxamine(Luvox®). 2D6/3A4 inhibitor (fluoxetine) Sigma action. Selective serotonin reuptake inhibitors are relatively selective in their action. Citalopram(Cipram®) Pharmacokinetics SSRIs are rapidly absorbed and metabolized by liver. Side effects of SSRIs stems from the effect of serotonin excess – nausea. There is also controversy about the increased risk of suicidality (associated with agitation/akathisia). Action Serotonin reuptake inhibitors are thought to work by first increasing somatodentritic concentration of serotonin. mood change and rarely. 1A2/3A4 inhibitor (fluvoxamine) Citalopram/escitalopram (which is the S-enantiomer of citalopram) is relatively selective for serotonin reuptake and do not demonstrate any appreciable effect in other receptors. insomnia. muscarinic antagonist. agitation. which causes a desensitization of 5HT-1A autoreceptor (i. vivid dreams. There are gastrointestinal symptoms and mood change (especially towards mania). It has low concentration in breast milk (except fluoxetine). All SSRIs have potent SRI effect. myoclonic jerks and hyperreflexia. Disequilibrium. vomiting. Sertraline(Zoloft®). Paroxetine(Seroxat®). as well as a range of other action such as: - Noradrenergic reuptake inhibitor. Hyperreflexia. 3D and 3S – Insomnia. I. pyrexia. clozapine and theophylline Fluoxetine and paroxetine interacts with P450 2D6 and 3A4. psychotic symptoms. akathisia. Parkinsonism and convulsion are rare but reported side effects. 5HT-2c agonist. general somatic symptoms.

phaeochromocytoma or hyperthyroidism. inhibition of which is linked to neuroprotection (e. patients with hepatic disease. broad bean pods and pickled herring. peripheral edema. yeast extracts. inhibition of which is linked to antidepressant (and hypertensive) effect. Action MAOIs irreversibly/reversibly (for moclobemide) binds to monoamine oxidase and inhibits their action. There are two forms of MAO. MAOIs are contraindicated in patients with cardiovascular and cerebrovascular diseases. Selegiline. some alcoholic drinks. The symptoms of hypertensive reaction are that of flushing. restlessness. MAOIs causes postural hypotension.Monoamine oxidase inhibitors Phenelzine. hung game. dizziness. nausea. MAO B. MAO A. Tranylcypromine. insomnia. or when they take drugs containing sympathomimetic amines such as phenylephrine. in epileptic patients. It increases concentration of virtually all amines and exerts their effect. in children. RIMA) Pharmacokinetics MAOIs are rapidly absorbed. headache. Moclobemide (Aurorix®/Manerix®. Inhibition of MAO B with MAO-B inhibitors has no antidepressant effect when MAO-B inhibitors is used at doses that are selective for MAO-B. sexual difficulties.g. increased blood pressure and rarely cerebral hemorrhage. Drug interactions MAOIs causes hypertensive reaction when the patient taking MAOIs are taking tyraminecontaining food such as cheese. sweating and tremor. MAOIs are third line agents for severe depression. . atypical depression as well as anxiety disorders. in parkinsonism). The only pharmacokinetic concern is that toxic levels can build up in slow acetylators – the other pharmacokinetic parameters are not important because the time of action is that of the time taken to replace stores of MAO (2 weeks) because except moclobemide all other MAOIs are irreversible inhibitors.

It also reduces craving associated with smoking cessation. Side effects of NRIs seem to involve noradrenaline effect on brain. 600mg/day) it has a high propensity (2%) of causing seizures. erythronhydrobupropion (half-life 33 hours). (Note that P450 2B6 also metabolises nicotine) Its inhibition effect with P450 2D6 also interferes with metabolism of TCA. anorexia nervosa or bulimia. apathy and notable cognitive disturbance (concentration and memory). Depression associated with fatigue. Thus. It is useful in patients whose depression does not respond to boosting serotonin by SSRIs. are theoretically more responsive to NRIs than of other drugs. phenothiazine type of antipsychotics. postural hypotension and urinary retention).1-0. Side effects includes dry mouth. cyclophosphamide and orphenadrine. theohydrobupropion (half-life 37 hours). The active metabolites are further metabolized into inactive metabolites and are excreted in the urine. sweating and hypertension. and are useful for treatment of noradrenergic deficiency syndrome (sometimes called ‘apathetic response’ to SSRI). tachycardia. At higher dose (e.Noradrenaline and Dopamine Reuptake Blockers Bupropion (Zyban®) Pharmacokinetics Bupropion is metabolized in liver into its three active metabolites. hydroxybupropion (half-life 20 hours). with a more potent dopamine reuptake effect than noradrenaline reuptake effect. Selective noradrenergic reuptake inhibitors Roboxetine Action Noradrenaline reuptake inhibitors are logical pharmacological complement to SSRIs. anxiety. insomnia. heart.g. Bupropion is known to decrease seizure threshold and thus is contraindicated in patients with epilepsy. . Class Ic antiarrhythmics and beta blockers. spinal cord. tremor. Drug interactions Bupropion is primarily metabolized by P450 2B6 isoenzyme (NOT 2D6). bupropion interferes with metabolism of thiotepa. Bupropion is generally activating/stimulating. GI tract and urinary bladder (insomnia. gastrointestinal disturbance.g.4%). Lower dose (e. Action Bupropion has both noradrenaline and dopamine reuptake inhibitor effect. 300-450mg/day) the propensity is decreased (0. and is not associated with bothersome sexual dysfunction that comes with SSRIs because bupropion lacks significant serotonergic component in its mechanism of action.

Tramadol is a kappa (of opiate receptor) agonist with SNRI activity which is used for treatment of pain. Sibutramine is used for treatment for obesity. Venlafaxine may cause significant discontinuation symptoms (I. Specialist supervision is required for initiation of venlafaxine in patients requiring more than 300mg/day. 3S’s) Duloxetine is also a 5-HT and NA reuptake inhibitor with weak inhibition of DA reuptake. Use carefully in patients with liver disease. 3D’s. It has positive effect on painful physical symptoms in patients with depression. – Dose . Venlafaxine is contraindicated in patients with high risk of severe ventricular arrhythmia and uncontrolled hypertension. duloxetine(Cymbalta®). and has a small DA reuptake inhibition effect seen only at higher doses. and in alcoholic patients this drug may prove harmful.Serotonin and noradrenergic reuptake inhibitors (SNRI) Venlafaxine (Effexor®). dopamine and noradrenergic reuptake inhibitor Venlafaxine has enhanced efficacy in severe depressive disorder. When dose exceeds 200 mg per day blood pressure need to be monitored. sibutramine(Reductil®). tramadol(Zydol®) Action Venlafaxine is a selective 5-HT and NA reuptake inhibitor. Pharmacologic action Serotonin reuptake inhibitor 150 mg Serotonin and noradrenergic reuptake inhibitor 300 mg Serotonin. Duloxetine cannot be used with alcohol.

When 5HT-2A receptor are blocked. These two agents block serotonin reuptake to a lesser extent than TCAs/SSRIs. causing release of noradrenaline. Dual serotonin 2 antagonists/serotonin reuptake inhibitors (Phenylpiperazines) Trazodone. it blocks the post-synaptic alpha-2 heteroreceptor in the presynaptic terminal of the serotoninergic neuron which causes release of more serotonin. the normal inhibiting influence on 5HT-1A receptor is lost. This sedation is possibly loss at higher doses of the medication because of enhanced noradrenergic effect. Nefazodone was withdrawn from the European market due to hepatotoxicity concerns. . Trazodone is somewhat sedative but can rarely cause priapism. It also reduces the side effect of enhanced serotonin outflow by blocking 5-HT2A. SARIs are relatively safe in overdose. which causes both direct effect on increase in noradrenaline level as well as secondary activation of alpha-1 receptor on serotonin neuron. 5HT-3 antagonist It blocks alpha-2 autoreceptor in its presynaptic membrane of the noradrenergic neuron. Its histamine-H1 antagonist action contribute to increased appetite and sedation. 2c and 3 receptors which mediates sexual dysfunction. nafazodone Action It blocks the serotonin 2A receptor as well as serotonin uptake. hence these drugs indirectly boost the effect of stimulating 5HT-1A receptors. In addition. This causes increase in firing of the serotoninergic neuron.Dual serotonin and noradrenaline action via alpha-2 antagonism Mirtazapine Action Mirtazapine has several action which allows its function to be actuated:alpha-2 antagonist histamine H1 antagonist 5HT-2A. gastrointestinal and nausea problems. 5HT-2c.