Anti-depressants II PDF - University of Baghdad 2022-2023

University of Baghdad College of Medicine 2022-2023 Title: Antidepressants II Grade:4th Grade Module: CP Speaker: Assistant Proff. Dr.Mohammed Qasim Al-Atrakji Date:15/3/2023 University of Baghdad/ College of Medicine 2022-2023 Learning Objectives Upon completion of this lectuer, you will be able to...

University of Baghdad College of Medicine 2022-2023 Title: Antidepressants II Grade:4th Grade Module: CP Speaker: Assistant Proff. Dr.Mohammed Qasim Al-Atrakji Date:15/3/2023 University of Baghdad/ College of Medicine 2022-2023 Learning Objectives Upon completion of this lectuer, you will be able to: 1. Describe the biogenic theory of depression. 2. Describe the therapeutic actions, indications, pharmacokinetics, contraindications, most common adverse reactions, and important drug–drug interactions associated with each class of antidepressant. 3. Discuss the use of antidepressants across the lifespan. 4. Compare and contrast the prototype drugs for each class of antidepressant with the other drugs in that class and with drugs in the other classes of antidepressants. University of Baghdad/ College of Medicine 2022-2023 Newer Drugs me Lofepramine-Has strong anti-cholinergic side-effect than amitriptyline and is less sedating; however, it may cause anxiety and insomnia.In overdose it is also less toxic than conventional tricyclics. Trazodone-Also has few anti-cholinergic side effects, but has strong sedating properties. mar 7 PPA p go I University of Baghdad/ College of Medicine 2022-2023 Monoamine oxidase inhibitors (MAOIs) Irreversibly or reversibly inhibits MAO, an enzyme found in nerves and other tissues (including the liver and GIT), to break down the biogenic amines NE, dopamine, and 5HT and relieve depression. (At one time, MAOIs were used more often, but now, they are used rarely because they require a specific dietary regimen to prevent toxicity). There are some patients, however, who only seem to respond to these particular drugs, so they remain available. Agents still in use include isocarboxazid (Marplan), phenelzine (Nardil), selegiline and tranylcypromine (Parnate). The choice of an MAOI depends on the prescriber’s experience and individual response. A patient who does not respond to one MAOI may respond to another. University of Baghdad/ College of Medicine 2022-2023 Mechanism of action Most MAOIs, such as phenelzine, form stable complexes with the enzyme, causing irreversible inactivation. This results in increased stores of norepinephrine, serotonin, and dopamine within the neuron and subsequent diffusion of excess neurotransmitter into the synaptic space. These drugs inhibit not only MAO in the brain but also MAO in the liver and gut that catalyzes oxidative deamination of drugs and potentially toxic substances, such as tyramine, which is found in certain foods. The MAOIs, therefore, show a high incidence of drug–drug and drug–food interactions. Selegiline administered as the transdermal patch may produce less inhibition of gut and hepatic MAO at low doses because it avoids first-pass metabolism. University of Baghdad/ College of Medicine 2022-2023 Actions Although MAO is fully inhibited after several days of treatment, the antidepressant action of the MAOIs, like that of the SSRIs, SNRIs, and TCAs, is delayed several weeks. Selegiline and tranylcypromine have an amphetamine-like stimulant effect that may produce agitation or insomnia. University of Baghdad/ College of Medicine 2022-2023 Therapeutic uses The MAOIs are indicated for depressed patients who are unresponsive or allergic to TCAs and SSRIs A special subcategory of depression, called atypical depression, may respond preferentially to MAOIs. Because of their risk for drug– drug and drug–food interactions, the MAOIs are considered last-line agents in many treatment settings. University of Baghdad/ College of Medicine 2022-2023 Pharmacokinetics The MAOIs are well absorbed from the GI tract, reaching peak levels in 2 to 3 hours. They are metabolized in the liver primarily by acetylation and are excreted in the urine Patients with liver or renal impairment and those known as “slow acetylators” may require lowered doses to avoid exaggerated effects of the drugs. The MAOIs cross the placenta and enter breast milk contraindicated in pregnancy University of Baghdad/ College of Medicine 2022-2023 Adverse Effects The MAOIs are associated with more adverse effects, more of which are fatal, than most other antidepressants.(The effects relate to the accumulation of NE in the synaptic cleft). Dizziness, excitement, nervousness, mania,hyperreflexia, tremors, confusion, insomnia, agitation,and blurred vision may occur. MAOIs can cause liver toxicity. Other GI effects can include nausea, vomiting, diarrhea or constipation, anorexia, weight gain, dry mouth, and abdominal pain. Urinary retention, dysuria, incontinence, and changes in sexual function may also occur. CV effects include orthostatic hypotension, arrhythmias, palpitations, angina, and the potentially fatal hypertensive crisis. (This last condition is characterized by occipital headache, palpitations, neck stiffness, nausea, vomiting,sweating, dilated pupils, photophobia, tachycardia, and chest pain. It may progress to intracranial bleeding and fatal stroke). University of Baghdad/ College of Medicine 2022-2023 Clinically Important Drug–Drug Interactions Drug interactions of MAOIs with other antidepressants include hypertensive crisis, coma, and severe convulsions with TCAs and a potentially life-threatening serotonin syndrome with SSRIs. (A period of 6 weeks should elapse after stopping an SSRI before beginning therapy with an MAOI). If MAOIs are given with other sympathomimetic drugs (e.g., methyldopa), sympathomimetic effects increase. Combinations with insulin or oral antidiabetic agents result in additive hypoglycemic effects. University of Baghdad/ College of Medicine 2022-2023 Clinically Important Drug–Food Interactions Tyramine and other pressor amines that are found in food, which are normally broken down by MAO enzymes in the GI tract, may be absorbed in high concentrations in the presence of MAOIs, resulting in increased blood pressure. In addition, tyramine causes the release of stored NE from nerve terminals, which further contributes to high blood pressure and hypertensive crisis. Patients who take MAOIs should avoid the tyramine containing foods such as aged cheeses and meats, chicken liver, pickled or smoked fish, and red wines (Phentolamine and prazosin are helpful in the management of tyramine-induced hypertension) drug of choice to antilapres University of Baghdad/ College of Medicine 2022-2023 The selective serotonin reuptake inhibitors (SSRIs) Group of antidepressant drugs that specifically inhibit serotonin reuptake, having 300- to3000-fold greater selectivity for the serotonin transporter, as compared to the norepinephrine transporter.( This contrasts with the tricyclic antidepressants (TCAs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) that nonselectively inhibit the reuptake of norepinephrine and serotonin. have little blocking activity at muscarinic, αadrenergic, and histaminic H1 receptors. Therefore, common side effects Moreover, the SSRIs associated with TCAs, such as orthostatic hypotension,sedation, dry mouth, and blurred vision, are not commonly seen with the SSRIs. Because they have different adverse effects and are relatively safe even in overdose, the SSRIs have largely replaced TCAs and monoamine oxidase inhibitors (MAOIs) as the of choice in treating depression. drugs University of Baghdad/ College of Medicine 2022-2023 SSRIs include fluoxetine (Prozac), the first SSRI citalopram (Celexa) escitalopram (Lexapro) fluvoxamine (Luvox) paroxetine (Paxil) sertraline (Zoloft) vilazodone (Viibryd). obese Patient SSRIs mix sideeffect we mi I University of Baghdad/ College of Medicine 2022-2023 Therapeutic Actions and Indications The action of SSRIs blocking the reuptake of 5HT increases the levels of 5HT in the synaptic cleft and may contribute to the antidepressant and other effects attributed to these drugs. SSRIs are indicated for the treatment of: Depression OCDs Panic attacks Bulimia Premenstrual dysphoric disorder (PMDD) Posttraumatic stress disorders Social phobias Social anxiety disorders. 4 weeks is necessary for realization of the full therapeutic effect. Patients may respond well to one SSRI and yet show little or no A period of up to response to another one. The choice of drug depends on the indications and individual response. I University of Baghdad/ College of Medicine 2022-2023 Pharmacokinetics All of the SSRIs are well absorbed after oral administration. Peak levels are seen in approximately 2 to 8 hours on average. Food has little effect on absorption (except with sertraline, for which food increases its absorption) Metabolized in the liver, and excreted in the urine and feces. Fluoxetine and paroxetine are potent inhibitors of a CYP450 isoenzyme (CYP2D6) responsible for the elimination of TCAs, antipsychotic drugs, and some antiarrhythmic and β-adrenergic antagonist drugs Contraindications and Cautions University of Baghdad/ College of Medicine 2022-2023 presence of allergy to any of these drugs because of the risk of hypersensitivity reactions. Caution in patients with impaired renal or hepatic function. with diabetes, which could be exacerbated by the stimulating effects of these drugs. Caution should also be used with severely depressed or suicidal patients, especially children and adolescents, because of a risk of increased suicidality. The SSRIs have been associated with congenital abnormalities in animal studies and should be used during pregnancy only if the benefits to the mother clearly outweigh the potential risks to the fetus.( Recent reports have linked use of SSRIs during pregnancy with pulmonary and cardiac problems in the newborn). The SSRIs enter breast milk and can cause adverse effects in the baby. University of Baghdad/ College of Medicine 2022-2023 Adverse Effects CNS effects: such as headache, drowsiness(Paroxetine and fluvoxamine), dizziness, insomnia(fluoxetine or sertraline), anxiety, tremor, agitation, and seizures. GI effects : such as nausea, vomiting, diarrhea, dry mouth, anorexia, constipation, and changes in taste often occur. GU effects: including painful menstruation, cystitis, sexual dysfunction, urgency,and impotence. (One option for managing SSRI-induced sexual dysfunction is to change the antidepressant to one with fewer sexual side effects, such as bupropion or mirtazapine. Alternatively, the dose of the drug may be reduced.) Respiratory changes: may include cough, dyspnea, upper respiratory infections, and pharyngitis. Other reported effects are sweating, rash, fever, and pruritus. Recent studies have linked the incidence of suicidal ideation and suicide attempts to the use of these drugs in pediatric patients and adolescents University of Baghdad/ College of Medicine 2022-2023 Clinically Important Drug–Drug Interactions Because of the risk of serotonin syndrome if SSRIs are used with MAOIs, this combination should be avoided,and at least 2 to 4 weeks should be allowed between use of the two types of drugs if one is switching from one to the other. In addition, the use of SSRIs with TCAs results in increased therapeutic and toxic effects. If these combinations are used, patients should be monitored closely ,and appropriate dose adjustments should be made. Discontinuation syndrome: (headache, malaise, and flu-like symptoms, agitation and irritability, nervousness, and changes in sleep pattern) All of the SSRIs have the potential to cause a discontinuation syndrome after their abrupt withdrawal,particularly the agents with shorter half-lives and inactive metabolites. Fluoxetine has the lowest risk discontinuation mar 9 mc.pt University of Baghdad/ College of Medicine 2022-2023 SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITORS(SNRIs) a Venlafaxine ,desvenlafaxine ,levomilnacipran and duloxetine inhibit the reuptake of both serotonin and norepinephrine. These agents, termed SNRIs, may be effective in treating depression in patients in whom SSRIs are ineffective. Furthermore, depression is often accompanied by chronic painful symptoms, such as backache and muscle aches, against which SSRIs are also relatively ineffective. This pain is, in part, modulated by serotonin and norepinephrine pathways in the central nervous system (CNS). Both SNRIs and the TCAs, with their dual inhibition of both serotonin and norepinephrine reuptake, are sometimes effective in relieving pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and low back pain. 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. ME University of Baghdad/ College of Medicine 2022-2023 ATYPICAL ANTIDEPRESSANTS The atypical antidepressants are a mixed group of agents that have actions at several different sites. This group includes : bupropion mirtazapine Nefazodone trazodone vilazodone vortioxetine University of Baghdad/ College of Medicine 2022-2023 Bupropion serotonin IN T 6 Bupropion is a weak dopamine and norepinephrine reuptake inhibitor that is used to alleviate the symptoms of depression. useful for decreasing cravings and attenuating withdrawal of nicotine in patients trying to quit smoking. It has a very low incidence of sexual dysfunction. Use of bupropion should be avoided in patients at risk for seizures or those who have eating disorders such as bulimia. Side effects: dry mouth, sweating, nervousness, tremor, and a dosedependent increased risk for seizures. University of Baghdad/ College of Medicine 2022-2023 Mirtazapine less incidence of sexual dysfunction Mirtazapine enhances serotonin and norepinephrine neurotransmission by serving as an antagonist at presynaptic α2 receptors. Additionally, some of the antidepressant activity may be related to antagonism at 5-HT2 receptors. It is sedating because of its potent antihistaminic activity, but it does not cause the antimuscarinic side effects of the TCAs, or interfere with sexual function like the SSRIs. Increased appetite and weight gain frequently occur. Mirtazapine is markedly sedating, which may be an advantage in depressed patients having difficulty sleeping. WHA Nefazodone and trazodone sedating University of Baghdad/ College of Medicine 2022-2023 These drugs are weak inhibitors of serotonin reuptake. Their therapeutic benefit appears to be related to their ability to block postsynaptic 5-HT2a receptors. Both agents are sedating, probably because of their potent histamine H1blocking activity. Trazodone is commonly used insomnia. off-label for the management of Trazodone has been associated with priapism. nefazodone has been associated with a risk for hepatotoxicity. Both agents also have mild to moderate α1 receptor antagonism, contributing to orthostasis and dizziness. University of Baghdad/ College of Medicine 2022-2023 in Vilazodone f Vilazodone is a serotonin reuptake inhibitor and a 5-HT1a partial agonist. Although the extent to which the 5-HT1a receptor activity contributes to its therapeutic effects is unknown, this possible mechanism of action renders it unique from that of the SSRIs. The adverse effect profile of vilazodone is similar to the SSRIs, including a risk for discontinuation syndrome if abruptly stopped. Vortioxetine Vortioxetine utilizes a combination of serotonin reuptake inhibition, 5-HT1a agonism, and 5-HT3 and 5-HT7 antagonism as its suggested mechanisms of action to treat depression.. The common adverse effects include : nausea, vomiting, and constipation, which may be expected due to its serotonergic mechanisms.