Antidepressants I, University of Baghdad, 2022-2023 PDF

University of Baghdad College of Medicine 2022-2023 Title: Antidepressants I Grade:4th Grade Module: CP Speaker: Assistant Proff. Dr.Mohammed Qasim Al-Atrakji Date:13/3/2023 Learning Objectives University of Baghdad/ College of Medicine 2022-2023 Upon completion of this lectuer, you will be able to:...

University of Baghdad College of Medicine 2022-2023 Title: Antidepressants I Grade:4th Grade Module: CP Speaker: Assistant Proff. Dr.Mohammed Qasim Al-Atrakji Date:13/3/2023 Learning Objectives University of Baghdad/ College of Medicine 2022-2023 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 Key words affect: feeling that a person experiences when he or she responds emotionally to the environment biogenic amine: one of the neurotransmitters norepinephrine, serotonin, or dopamine; it is thought that a deficiency of these substances in key areas of the brain results in depression depression: affective disorder in which a person experiences sadness that is much more severe and longer lasting than is warranted by the event that seems to have precipitated it, with a more intense mood. University of Baghdad/ College of Medicine 2022-2023 monoamine oxidase inhibitor (MAOI): drug that prevents the enzyme monoamine oxidase from breaking down norepinephrine(NE), leading to increased NE levels in the synaptic cleft; relieves depression and also causes sympathomimetic effects selective serotonin reuptake inhibitor (SSRI): drug that specifically blocks the reuptake of serotonin and increases its concentration in the synaptic cleft; relieves depression and is not associated with anticholinergic or sympathomimetic adverse effects tricyclic antidepressant (TCA): drug that blocks the reuptake of norepinephrine and serotonin; relieves depression and has anticholinergic and sedative effects tyramine: an amine found in food that causes vasoconstriction and raises blood pressure; ingesting foods high in tyramine while taking an MAOI poses the risk of a severe hypertensive crisis University of Baghdad/ College of Medicine 2022-2023 Depression is a very common affective disorder involving feelings of sadness that are much more severe and longer lasting than the suspected precipitating event, and the mood of affected individuals is much more intense University of Baghdad/ College of Medicine 2022-2023 Patients who are depressed may have little energy, sleep disturbances, a lack of appetite, limited libido, and inability to perform activities of daily living. They may describe overwhelming feelings of sadness, hopelessness, and disorganization. University of Baghdad/ College of Medicine 2022-2023 Clinical depression is a disorder that can interfere with a person’s family life, job, and social interactions. Left untreated, it can produce multiple physical problems that can lead to further depression or, in extreme cases, even suicide. University of Baghdad/ College of Medicine 2022-2023 University of Baghdad/ College of Medicine 2022-2023 Biogenic Amine Theory of Depression depression results from a deficiency of biogenic amines in key areas of the brain; these biogenic amines include norepinephrine (NE), dopamine, and serotonin (5HT). University of Baghdad/ College of Medicine 2022-2023 Both NE and 5HT are released throughout the brain by neurons that react with multiple receptors to regulate arousal, alertness, attention, moods, appetite, and sensory processing. University of Baghdad/ College of Medicine 2022-2023 Deficiencies of these neurotransmitters may develop depression µ First, monoamine oxidase(MAO) may break them down to be recycled or restored in the neurons. Second, rapid fire of the neurons may lead to their depletion. Third, the number or sensitivity of postsynaptic receptors may increase, thus depleting neurotransmitter levels. Depression also may occur as a result of other, yet unknown causes. University of Baghdad/ College of Medicine 2022-2023 Supported by: pharmacological effect of antidepressants (TCA, MAOI) In the past, medication of hypertension with reserpine induced depression Contradiction: several drugs (e.g. cocaine) increase the amount of these neurotransmitters in the CNS but are unable to treat depression the effect of antidepressants on neurotransmitter levels is relatively quick but onset of antidepressant action is significantly delayed University of Baghdad/ College of Medicine 2022-2023 3 Receptor theory“ = the problem is in up-regulation of post-synaptic receptors and alterations in their sensitivity The antidepressant treatment increases the amount of monoamines in CNS and thereby gradually normalize the density/sensitivity of their receptors The precise pathophysiology of depression remains unsolved University of Baghdad/ College of Medicine 2022-2023 Therapy of depression Pharmacotherapy/Mood Elevators Tricyclic antidepressants (TCA) Monoamine oxidase inhibitors (MAOI) Selective Serotonin Re-uptake Inhibitors (SSRI) Other and atypical antidepressant Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) Noradrenaline and Dopamine Reuptake Inhibitors (NDRI) Noradrenaline Reuptake Inhibitors (NaRI) Noradrenergic/Specific Serotonergic Antidepressants (NaSSA) Duration of treatment – 6 months after recovery (1st epizode), may be even life-long treatment in recurrent depression Non-pharmacological treatment Psychotherapy Light therapy Electroconvulsive therapy (ECT) Drug Therapy University of Baghdad/ College of Medicine 2022-2023 The use of agents that alter the concentration of neurotransmitters in the brain is the most effective means of treating depression with drugs University of Baghdad/ College of Medicine 2022-2023 The antidepressant drugs used today counteract the effects of neurotransmitter deficiencies in three ways: First, they may inhibit the effects of MAO, leading to increased NE or 5HT in the synaptic cleft. Second, they may block reuptake by the releasing nerve, leading to increased neurotransmitter levels in the synaptic cleft. Third, they may regulate receptor sites and the breakdown of neurotransmitters, leading to an accumulation of neurotransmitter in the synaptic cleft. University of Baghdad/ College of Medicine 2022-2023 I. Tricyclic Antidepressants (TCAs) Chemical structure with characteristic three-ring nucleus – lipophilic nature Originally developed as antipsychotics (1949), but were found to have no effect in this indication. imipramine Principal mechanism of action: blockade of re-uptake of monoamine neurotransmitters noradrenaline (NA) and serotonin (5-HT) by competition for binding site of the carrier protein. 5HT and NA neurotransmission is similarly affected but the effect on the dopamine system is much less important (compare with cocaine) in most TCA, other receptors (incl. those outside the CNS) are also affected: blockade of H1-receptor, -receptors, M-receptors University of Baghdad/ College of Medicine 2022-2023 University of Baghdad/ College of Medicine 2022-2023 Pharmacological action CNS-mood elevation in depress patient,can cause ataxia,epilepsy,seizures,sedation and coma CVS-orthostatic hypotension ANS-anticholinergic effects.Most potent anticholinergic action University of Baghdad/ College of Medicine 2022-2023 TCAs that are available include: we the amines amitriptyline (generic),amoxapine (Asendin), clomipramine (Anafranil), doxepin (Sinequan), imipramine (Tofranil), and trimipramine (Surmontil); 1 2 516 the secondary amines desipramine (Norpramin), nortriptyline (Aventyl, Pamelor), and protriptyline (Vivactil); tetracyclic drug maprotiline (generic). Patients who do not respond to one TCA may benefit from a different drug in this University of Baghdad/ College of Medicine 2022-2023 Clinical use and efficacy is relatively close within the group the more significant difference is in their adverse effects Indications atria on University of Baghdad/ College of Medicine 2022-2023 Clinical depression (The sedative effects of these drugs may make them more effective in patients whose depression is characterized by anxiety and sleep disturbances) Neuropathic pain -Diabetic neuropathy/Analgesia and prevention of migraine headache it ADHD (Attention deficit hyperactivity disorder) Nocturnal Enuresis (Imipramine) Some are effective for treating enuresis in children older than 6 years(largely been replaced by desmopressin) Panic disorder(Imipramine) OCD (obsessive–compulsive disorders) Clomipramine is effective. Others like eating disorder, narcolepsy University of Baghdad/ College of Medicine 2022-2023 Pharmacokinetics Administered orally – rapid absorption, however extensive first pass effect  low and inconsistent BAV Strong binding to plasma proteins (90-95% bound). They are also bound in tissues + wide distribution (high lipophilicity) = large distribution volumes (ineffectiveness of dialysis in acute intoxications). Biotransformation – in the liver (CYP450, N-demethylation and tricyclic ring hydroxylation) – most of these metabolites are active! CYP450 polymorphisms ! Glucuronidation inactive metabolites excreted in the urine. University of Baghdad/ College of Medicine 2022-2023 Adverse Effects Pharmacological Action Adverse Effect Muscarinic receptor Blockage/ Anticholinergic Dry mouth, tachycardia, blurred vision, glaucoma Constipation, Urinary retention, Sexual dysfunction Cognitive impairement ᾴ1 Adrenoceptor blockade Drowsiness, Postural Hypotension, Sexual dysfunction(loss of libido, impaired erection) Cognitive Impairement Histamine H1 receptor Blockade Drowsiness, Weight Gain Membrane stabilizing properties Cardiac conduction defects, Cardiac arrythmia, Seizures Others Rash, Oedema, Leukopenia, Elevated liver enzymes Eation 9s University of Baghdad/ College of Medicine 2022-2023 Contraindications Allergy to any of the drugs in this class because of the risk of hypersensitivity reactions. Recent myocardial infarction because of the potential occurrence of reinfarction or extension of the infarct with the cardiac effects of the drug, Myelography within the previous 24 hours or in the next 48 hours because of a possible drug– drug interaction with the dyes Concurrent use of an MAOI because of the potential for serious adverse effects or toxic reactions. Pregnancy and lactation are contraindications because of the potential for adverse effects in the fetus and neonate; (TCAs should not be used unless the benefi t to the mother clearly outweighs the potential risk to the neonate.) University of Baghdad/ College of Medicine 2022-2023 Cautions Patients with preexisting cardiovascular (CV) disorders because of the cardiac stimulatory effects of the drug Any condition that would be exacerbated by the anticholinergic effects, such as angle-closure glaucoma, urinary retention, prostate hypertrophy, or GI or genitourinary (GU) surgery. Psychiatric patients, who may exhibit a worsening of psychoses or paranoia Manic–depressive patients, who may shift to a manic stage. There is a black box warning on all of the TCAs bringing attention to a risk of Suicidality, especially in children and adolescents. (Caution should be used, and the amount of drug dispensed at any given time should be limited with potentially suicidal Patients). Patients with a history of seizures because the seizure threshold may be decreased The presence of hepatic or renal disease, which could interfere with metabolism and excretion of these drugs and lead to toxic levels University of Baghdad/ College of Medicine 2022-2023 Drug Dose It takes about 2-3 weeks before tricyclic antidepressents has any evident action on depression Hence, it is useless to give it as per needed only.They must be administred regularly in sufficient doses to achieve the desired effect. After remission of symptoms, it is essential to continue the anti-depressents for 6-12 months in the 1st episode and longer duration in subsequent episodes to prevent reccurence of symptoms.. University of Baghdad/ College of Medicine 2022-2023 When starting the drug start with a low dose and gradually increase it to prevent the side-effects. When stopping the drug, taper the dose over 2-3 weeks period. As if you were to stop it abruptly, it will cause withdrawal symptoms such as: -Nausea -Tremor -Headache -Insomnia University of Baghdad/ College of Medicine 2022-2023 Clinically Important Drug–Drug Interactions If TCAs are given with cimetidine, fl uoxetine, or ranitidine,an increase in TCA levels results, with an increase in both therapeutic and adverse effects, especially anticholinergic conditions The combination of TCAs and oral anticoagulants leads.to higher serum levels of the anticoagulants and increased risk of bleeding. If TCAs are combined with sympathomimetics or clonidine, the risk of arrhythmias and hypertension is increased. This combination should be avoided, especially in patients with underlying CV disease. The combination of TCAs with MAOIs leads to a risk of severe hyperpyretic crisis with severe convulsions,hypertensive episodes, and death.( Although TCAs and MAOIs have been used together in selected patients who do not respond to a single agent, the risk of severe adverse effects is very high.)