Lesson 11 Antidepressant Drugs PDF

Lesson 11 Antidepressant drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. Introduction 2. Tricyclic antidepressants (TCA) 3. Selective serotonin reuptake inhibitors (SSRI) 4. Mono amino oxidase inhibitors (MAOI) 5. Serotonin and Noradrenalin...

Lesson 11 Antidepressant drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. Introduction 2. Tricyclic antidepressants (TCA) 3. Selective serotonin reuptake inhibitors (SSRI) 4. Mono amino oxidase inhibitors (MAOI) 5. Serotonin and Noradrenaline reuptake inhibitors (SNRI) 6. Others Noradrenaline uptake inhibitors -Bupropion,Reboxetine,Atomoxetine -Natural compounds 7. Monoamine receptor Antagonists 8. Melatonin Agonist 9. Drug for the treatment of Bipolar disorder  Depression It is a mood disorder that is manifested by alterations in the cognitive, behavioral and emotional spheres. It is a long-term disease. It is a disease that can be treated and cured. Anyone can suffer from it at a certain time in their life. It has to be treated by a specialist. Depression is a disease, not a weakness.  Depression Symptoms EMOTIONAL SYMPTOMS:  Apathy, pessimism, sadness BIOLOGICAL SYMPTOMS:  Low self-esteem.  Sleep disorders.  Loss of motivation.  Loss of appetite.  Suicidal thoughts.  Delayed thinking and action.  Loss of libido. Other common forms of depression: Postpartum depression; Premenstrual disorder; Affective emotional disorder.  Treatment of depression ► Prevention ► Psychotherapy (mild depression) ►Psychotherapy + pharmacological treatment (moderate depression) ► Hospitalization (severe depression) ► ECT (Electroconvulsive Therapy)  Treatment of depression PHARMACOLOGICAL TREATMENT Currently, depression is associated with a decrease in the release of neurotransmitters in the synapse, especially Dopamine and 5-HT. TREATMENT PHASES: 1) Remission phase: It takes 2-4 weeks for antidepressants to start working. 2) Continuation phase: 6-12 months. 3) Maintenance phase: depends on evolution of the desease Mechanism of depression onset: Prodepressive Antidepressive pathways pathways involve the involve NA 5- hypothalamic HT, and BNDF and pituitary adrenal axis *BDNF:Brain-Derived Neurotrophic Factor  Classification of antidepressants According to its mechanism of action Tricyclic antidepressants(TCA) = non-selective amine reuptake inhibitors Selective serotonin reuptake inhibitors (SSRIs) Monoamine oxidase inhibitors (MAOI-A y B) Serotonin and Noradrenaline Uptake Inhibitors (SNRIs) Others Treatment of depression TCA ►Non-selective amine reuptake inhibitors/ heterocyclic antidepressants/ tricyclic antidepressants (TCA): Imipramine, Desipramine, Amitriptyline, Nortriptyline, Clomipramine And Doxepin Mechanism of action:They inhibit the reuptake of NA, and Serotonin (less Dopamine) in the synapse cleft, thus increasing its concentration in it.  anticholinergic receptors (2 types): Treatment of depression - antimuscarinic - antinicotinic TCA Mechanism of action: block the uptake of amines – inhibit noradrenaline and 5-HT uptake (less effect on dopamine uptake) improvement of emotional symptoms: enhancement of 5-HT relief of biological symptoms: facilitation of noradrenergic transmission.(α receptors) TCAs affect other receptors – The antimuscarinic effects are responsible of various side effects Treatment of depression TCA Pharmacokinetics ►Highly liposoluble drugs Good distribution (BBB) ► Taken orally, in progressively increasing doses. ► They are fixed to plasma proteins. ► Hepatic metabolisation. Active metabolites. ► Long elimination half-life (10-80 h) – even longer in elderly patients. – developing side effects. Treatment of depression TCA Pharmacological actions: Antidepressant. The antidepressant action is seen during the first 4 weeks of treatment. improves sleep, appetite, psychomotor activity. By the fourth week, depressed mood and feelings of despondency and hopelessness improve. Anxiolytic and sedative action Analgesic action, especially in chronic pain, when pain is part of the somatization of depression. (Some TCAs are also used to treat neuropathic pain) Treatment of depression TCA ADRs  Cardiovascular: Orthostatic hypotension, palpitations, tachycardia. Antimuscarinic Effect: (like atropine, because TCA have antagonist action on M receptors) Dry mouth, constipation, urinary retention, nasal congestion. blurred vision...  Neurological: tremors in hands and head. Other: Weight gain, excessive sweating, photosensitivity, gastrointestinal discomfort. Intoxication: Overdose is common due to the suicidal tendency of some depressive patients Arrhythmias → convulsions → coma. Treatment of depression Drug interactions TCA Pharmacodynamic interaction: - They enhance the actions of catecholamines. - They enhance the actions of MAOI Monoamine oxidase inhibitors Pharmacokinetic interaction: − They increase the activity of oral anticoagulants (warfarin) and increase the risk of bleeding. (PP-binding) − Oral contraceptives inhibit metabolism of TCAs (metabolism) − TCAs potentiate the effects of alcohol and anaesthetic agents (not known): death may occur − interfere with antihypertensive drugs Treatment of depression TCA Therapeutic applications  Depressive syndromes.  Anxiety syndromes (panic attacks).  Hyperactivity syndrome, imipramine. Treatment of enuresis: Children > 5 years old (imipramine)  Pain: Neurogenic (phantom limb syndrome ). Oncological, headaches... Phantom limb syndrome is a condition where a person feels sensations, often painful, in a part of the body that has been amputated or removed. Treatment of depression SSRI ► Selective Serotonin Reuptake Inhibitors (SSRIs): Fluoxetine, Paroxetine, Citalopram, Sertraline Mechanism of action: inhibition of the reuptake of Serotonin in the synapse cleft, thus increasing its concentration in it. Treatment of depression SSRI Most commonly antidepressant prescribed Fewer side effects than TCAs (cardiac) Less effective than TCAs in severe depression Just as effective as TCAs and MAOIs in treating moderate depression. Pharmacokinetics: Orally Half-life: 15-24 h. (Fluoxetine 24-96 h) Fluexetine and paroxetine are not used in combination with TCAs because they decrease TCA’s hepatic metabolism and may increase the toxicity Treatment of depression SSRI ADRs nausea, anorexia, insomnia, loss of libido In combination with MAOIs, SSRIs can cause a ‘serotonin syndrome’ – tremor, hyperthermia and cardiovascular collapse and death. not recommended in children under 18 (agressivity…suicidal thoughts) They are relatively safe in overdose, compared with TCAs – but can develop ventricular arrhythmias and risk of sudden death. Treatment of depression SSRI Therapeutic applications: ✓ Very useful in the elderly and cardiac patients who do not tolerate tricyclics and derivatives. ✓ Treatment of obsessive-compulsive disorders. ✓ In bulimia. ✓ Panic attacks. ✓ Premenstrual dysphoric disorder. ✓ Premature ejaculation disorder ✓ Migraines Treatment of depression MAOI MonoAmino Oxidase Inhibitors (MAOI-A and B): Non-selective (irreversible): Phenelzine, Tranylcypromine ,Iproniazid, Pargilin. MAOI-A selective (reversible): Moclobemide. Mechanism of action: MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. -MAO-A: preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine and other trace amines, like tyramine, whereas dopamine is equally deaminated by both types. MAO-B: preferentially deaminates phenethylamine and certain other trace amines Treatment of depression MAOI MonoAmino Oxidase Inhibitors (MAOI-A and B) MAO-A – main target for the antidepressant MAOIs. MAO-B – Selegiline (selectively inhibitor) , used in the treatment of Parkinson’s disease. Their binding with the enzyme is covalent, and it takes several weeks to recover. Treatment of depression Pharmacokinetics MAOI They are well absorbed orally. They are metabolized in the liver Short elimination half-life Multiple daily doses The therapeutic effect takes between 1 and 3 weeks to appear. Its use is limited by its toxicity and drug interactions. ADRs Hypotension orthostatic is a common side effect. Excessive central stimulation may cause tremors, excitement, insomnia and, in overdose, convulsions. Increased appetite Treatment of depression MAOI Drug interactions Tyramine Hypertensives crisis. Normally tyramine is metabolized by MAO. Its increase induces the release of NA and vasoconstriction “Cheese effect” if you consume foods rich in tyramine (such as aged cheeses, red wine, beer, cured meats and fermented foods). Symptoms of a hypertensive crisis include: Severe headache Chest pain Nausea and vomiting Excessive sweating Tachycardia or irregular heartbeat Risk of stroke Treatment of depression MAOI Drug interactions SSRIs or TCA serotininergic syndrome Enhancement of the depressant actions of other drugs: sympathomimetics, antihistamines, opioids... THERAPEUTIC APPLICATIONS: Reserve antidepressants, for when tricyclics and derivatives fail or in cases of atypical depression. Treatment of depression SNRI Serotonin and Noradrenaline Uptake Inhibitors (SNRIs) non-selective for 5-HT and NA uptake. Venlafaxine, Desvenlafaxine and Duloxetine – extensively used antidepressant drugs effective in some anxiety disorders. – may be useful in treating some perimenopausal symptoms (hot flushes and insomnia) – Duloxetine is also used in the treatment of neuropathic pain and fibromyalgia (pleasure pathways) and urinary incontinence (noradrenergic trasmission) 28 Treatment of depression SNRI Pharmacokynetics: They are all active orally. venlafaxine is available in a slow-release formulation that reduces the incidence of nausea. ADRs headache, insomnia, sexual dysfunction, dry mouth, dizziness, sweating and decreased appetite (Noradrenergic transmission) in overdose: CNS depression, serotonin toxicity, convulsions and cardiac conduction abnormalities. Duloxetine has been reported to cause hepatotoxicity – contraindicated for patients with hepatic impairment. 29 Treatment of depression Other Noradrenaline Uptake Inhibitors Bupropion – inhibits both noradrenaline and dopamine – Not abuse potential. – It is also used to treat nicotine dependence. – At high doses it may induce seizures. Reboxetine and Atomoxetine – highly selective of NA uptke (their efficacy in depression is less than TCAs). Atomoxetine is used in the treatment of: – attention deficit/ hyperactivity disorder 29 Treatment of depression Others: Natural compounds Hypericum perforatum The herbal preparation of St John’s wort, whose main active ingredient is Hyperforin. -Inhibition of the reuptake or 5-HT, Dopamine, NA, GABA and glutammate -Antidepressive and anxiolytic effect Treatment of depression Monoamine Receptor Antagonists Mirtazapine – Blocks alfa 2 , 5-HT2C (antidepressant effects) and H1 receptors Trazodone combines 5-HT2A and 5-HT2C receptor antagonism with 5-HT reuptake inhibition. Treatment of depression Melatonin Agonist Agomelatine It is an agonist of MT1 and MT2 receptors and has a short biological half-life – to treat severe depression, usually taken once daily before bed. – It may work by correcting disturbances in circadian rhythms It is related to hepatotoxicity Treatment of depression Electroconvulsive therapy electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (TMS):for patients who have not responded to antidepressant drugs. – ECT appears to be an effective treatment for severe suicidal depression It often causes confusion and memory loss lasting for days or weeks. – TMS :less effective Treatment of depression Antidepressants CLINICAL USES SUMMARY Mild depression is often best treated initially with non-drug measures. The use of antidepressant drugs is advisable in the treatment of moderate to severe depression. The clinical efficacy of antidepressant drugs is limited, and varies between individuals. Different classes of antidepressant drugs have similar efficacy but different side effects. Choice of drug is based on individual aspects including concomitant disease. Other things being equal, an SSRI is preferred as these are usually better tolerated and are less dangerous in overdose. Antidepressant drugs take several weeks before taking effect, so decisions on dose increment or switching to another class should not be made precipitately. Use of MAOIs is by specialists. An effective regimen should be continued for at least 2 years. In urgent situations, specialist consideration should be given to possible use of electroconvulsive therapy. Anxiolytic (e.g. benzodiazepine), or antipsychotic drugs are useful adjuncts in some patients.  Bipolar Disorder Bipolar disorder is a mental health condition marked by extreme mood swings, including episodes of mania and depression. These phases can significantly impact behavior, energy levels, and daily functioning. Treatment of Bipolar Disorder LITHIUM SALTS: Lithium carbonate Pharmacokinetics. Orally It is excreted by kidney. Narrow therapeutic margin (monitoring of the plasma concentration is essential.) Mechanism of action:Unknown. It is effective in both the manic and depressive phases, which is why it is considered a stabilizer. It increases the release of NA and 5-HT in the brain. beneficial effects in neurodegenerative diseases such as Alzheimer’s disease Treatment of Bipolar Disorder LITHIUM SALTS: Lithium carbonate ADRs Gastric discomfort, nausea, vomiting, diarrhea. Anorexia. Weight gain. Polyuria, Thirs: resulting from inhibition of the action of antidiuretic hormone. Trembling hands. In chronic administrations: Thyroid disorders. Kidney disorders. In the first months of pregnancy, it can induce fetal malformations Treatment of Bipolar Disorder LITHIUM SALTS: Lithium carbonate Therapeutic applications: Lithium is the drug of first choice in the control of manic phases and in the prophylaxis of bipolar disorder. treatment Doses should be adjusted to the characteristics of each patient Lithium carbonate improves 70% of maniac-depressive (bipolar) disorders, although the effect takes 1-2 weeks to appear Treatment of Bipolar Disorder ANTIEPILEPTIC DRUGS Carbamazepine, Valproate, Lamotrogine – fewer side effects than lithium and have proved efficacious in the treatment of bipolar disorder. Valproate and carbamazepine are effective in treating acute attacks of mania and in the long-term treatment of the disorder. Lamotrogine is effective in preventing the recurrence of both mania and depression. Carbamazepine: Enzyme inducer Valproic acid (valproante): very teratogenic -->spina bifida Treatment of Bipolar Disorder ATYPICAL ANTIPSYCHOTIC DRUGS Olanzapine, Risperidone, Quetiapine, Aripiprazole are second-generation drugs developed for the treatment of schizophrenia – These agents are antagonist of D2-dopamine and 5-HT2Areceptor. – effective against mania – against bipolar depression:in combination with lithium or valproate. – Olanzapine is given in combination with the antidepressant fluoxetine. Haloperidol: is indicated for the prophylaxis of maniac-depressive disease Treatment of Bipolar Disorder Summary Questions?????