Pharmacology of Serotonergic and Central Adrenergic Neurotransmission PDF

PHARMACOLOGY OF SEROTONERGIC AND CENTRAL ADRENERGIC NEUROTRANSMISSION Week 9 Dr. Fatemah Alherz 1 Processes Regulated by Serotonin and NE Pathways A wide variety of behavioral and psychological processes are regulated by these two neurotransm...

PHARMACOLOGY OF SEROTONERGIC AND CENTRAL ADRENERGIC NEUROTRANSMISSION Week 9 Dr. Fatemah Alherz 1 Processes Regulated by Serotonin and NE Pathways A wide variety of behavioral and psychological processes are regulated by these two neurotransmitters These pathways are central to the modulation of mood, the sleep-wake cycle, motivation and reward, cognitive processing, pain perception, neuroendocrine function, and a number of other physiologic processes. 2  Processes Regulated by Serotonin Pathway Pathological Conditions & Drugs Clinical conditions associated with disturbed NE and 5- HT include migraine, depression, anxiety, and irritable bowel syndrome. Interventions in this pharmacologic group involve antipsychotic and antidepressant drugs 4 Synthesis of Serotonin 5 The serotonin metabolic cycle 6  Vesicular monoamine transporter )VMAT( Is a non-specific monoamine transporter important for vesicular packaging of DA, Epi, & 5HT Inhibited by reserpine 7  Re-uptake Transporters Monoamines are transported from the extracellular space back to the presynaptic neuron by selective transporters: SERT – Serotonin transporter NET – NE transporter DAT – Dopamine transporter These also transport the other monoamines but less efficiently. 8  Fate of re-taken up Monoamines Once returned by the transporters, the monoamines can be: – Stored again by (VMAT) or – Degraded by Monoamine oxidase – MAO 9  MAO and COMT MOAs – MAO-A: oxidizes 5HT, NE, DA – MAO-B: preferentially oxidizes DA COMT (catechol-O-methyl transferase – In extracellular space – Less significant role in the CNS than it does peripherally 10  Serotonin Receptors 15 types of 5HT receptor, all but one are G-protein coupled 11  Serotonin Receptors 5HT-1 –Inhibit cellular activity via Gi pathway cAMP & >> opening K channels. Inhibitory receptor 12  Serotonin Receptors 5HT-2 Increase signaling through the Gq pathway to cause phosphatidylinositol (PI) turnover 5-HT2A and 5-HT2C signaling is excitatory and lowers the threshold for neuronal firing. 13  Serotonin Receptors 5HT-4,6,&7 – Through Gs pathway – Stimulate adenylyl cyclase – Stimulates intestinal activity (i.e., prokinetic action) 14  Serotonin Receptors 5-HT3 the only known ligand gated ion channel 15 PATHOPHYSIOLOGY OF AFFECTIVE DISORDERS Major depressive disorder (MDD) and bipolar disorder (BD) are characterized by mood dysregulation. MDD is typified by single or recurrent depressive episodes, whereas BD is defined by the presence of mania or hypomania as well as periods of depression. 16 The Monoamine Hypothesis of Depression ➼This hypothesis suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin and norepinephrine. ➼Evidence for this hypothesis is based on the unexpected effects on mood of imipramine, iproniazid, and reserpine. 17 The Monoamine Hypothesis of Depression ➼The tricyclic drug imipramine was developed to treat psychotic patients, but it was subsequently noted to have strong antidepressant effects. ➼Imipramine preferentially blocks the 5-HT transporter (SERT), and its active metabolite desipramine preferentially blocks the NE transporter (NET). ➼By these mechanisms, imipramine allows 5-HT and NE to persist in the extracellular space at higher concentrations and for longer durations, yielding increased activation of 5- HT and NE receptors. 18  The Monoamine Hypothesis of Depression The antituberculosis drug iproniazid was shown to have antidepressant effects. Iproniazid inhibits monoamine oxidase (MAO), thereby preventing 5-HT, NE, and DA degradation. The resulting increase in cytosolic neurotransmitters leads to increased neurotransmitter uptake into vesicles and, consequently, to greater release of neurotransmitters after exocytosis. 19  The Monoamine Hypothesis of Depression the antihypertensive agent reserpine was noted to induce depression in 10–15% of patients. Reserpine depletes 5-HT, NE, and DA in presynaptic neurons by inhibiting the transport of these neurotransmitters into synaptic vesicles. The drug binds irreversibly to VMAT and ultimately destroys the vesicles. The 5-HT, NE, and DA that accumulate in the cytoplasm are degraded by mitochondrial MAO. Which leads to decrease in monoamine neurotransmission is thought to be responsible for inducing a depressed mood. 20  Limitations of the Monoamine Theory Although nearly all of antidepressants are pharmacologically active at their molecular and cellular sites of action almost immediately, their full antidepressant effects are generally not seen until the drugs have been administered for 6 or more weeks of continuous treatment. Although reserpine rapidly depletes neurotransmitters in monoaminergic systems, it takes several weeks of continuous treatment with reserpine to induce depression. In some patients, drugs that selectively increase 5-HT neurotransmission decrease depressive symptoms, while drugs that selectively increase NE neurotransmission have little or no effect. In other patients, drugs affecting the NE system are more beneficial than those affecting the 5-HT system. 21 Limitations of the Monoamine Theory cont. Overall, each individual drug is effective in about 70% of patients with depression, and drugs that have markedly different efficacies in blocking the reuptake of NE and/or 5-HT may have similar clinical effectiveness when tested in large populations. 22 PHARMACOLOGIC CLASSES AND AGENTS 23 Pharmacologic Classes of Drugs in Disorders of the Serotonin / NE pathways 24  Interfere with the ability of synaptic vesicles to store monoamines Displace 5HT, DA, and NE from their storage vesicles in presynaptic nerve terminals 1-Inhibitors of serotonin E.g. amphetamines, methylphenidate, dextroamphetamine storage Widely used in the treatment of attention- deficit hyperactivity disorder (ADHD) Second line antidepressant 25 26  Old MAO inhibitor are irreversible and non- selective MAOIs Phenelzine 2-Inhibitors Newer MAOIs (Reversable inhibitor of of serotonin MAO-A (RIMAs) degradation Moclobemide Selective MAO-B inhibitor (at low doses) Selegiline 27  MAOI By inhibiting the degradation of monoamines, MAOIs increase the 5-HT and NE available in the cytoplasm of presynaptic neurons. The increase in cytoplasmic levels of these monoamines leads to increased uptake and storage of 5-HT and NE in synaptic vesicles and some constitutive leakage of the monoamines into the extracellular space. Their full antidepressant effects are generally not seen until the drugs have been administered for 6 or more weeks of continuous treatment. 28  Adverse effects of MAOI The most toxic adverse effect of MAOI use is systemic tyramine toxicity (especially with older MAOIs). Because GI and hepatic MAO metabolize tyramine, consumption of foods that contain tyramine, such as processed meats, aged hard cheeses, and red wine, can lead to excess levels of circulating tyramine Tyramine is an indirect sympathomimetic that can stimulate the release of large amounts of stored catecholamines by reversing the reuptake transporters. This uncontrolled catecholamine release can induce a hypertensive crisis characterized by headache, tachycardia, nausea, cardiac arrhythmia, and stroke. 29 3- Reuptake Inhibitors 30  3- Reuptake Inhibitors These drugs alleviate the symptoms of a variety of common psychiatric conditions, including depression, anxiety, and obsessive-compulsive disorders. Four classes of reuptake inhibitors are in use: 1-The nonselective tricyclic antidepressants (TCAs) 2- Selective serotonin reuptake inhibitors (SSRIs) 3- Serotonin-norepinephrine reuptake inhibitors (SNRIs) 4- The newer norepinephrine selective reuptake inhibitors (NRIs). 31  Tricyclic antidepressants (TCAs) E.g. Amitriptyline, – TCAs inhibit the reuptake of 5-HT and NE from the extracellular space by blocking 5-HT and NE reuptake transporters, respectively. – Because the increased time spent by neurotransmitters in the extracellular space leads to increased receptor activation, the reuptake inhibitors cause enhancement of postsynaptic responses. 32 Tricyclic antidepressants (TCAs) Used to manage: Obsessive-compulsive disorder Pain syndromes (at lower doses) Prophylaxis for migraine 33  Tricyclic antidepressants (TCAs) Adverse effects: The adverse effect profile of TCAs results due to their ability to bind a number of channels and receptors in addition to their therapeutic targets. TCAs can also act as antagonists at muscarinic (cholinergic), histamine, adrenergic, and dopamine receptors. The anticholinergic effects : nausea, vomiting, anorexia, dry mouth, blurred vision, constipation, tachycardia, and urinary retention. The antihistaminergic effects include sedation, weight gain, and confusion (in the elderly) The antiadrenergic effects include orthostatic hypotension, is an especially significant risk or elderly patients. 34  2-Selective Inhibitors of Serotonin reuptake (SSRIs) – At low doses, SSRIs are believed to bind primarily to 5-HT transporters. – At high doses can also bind NE transporter – E.g. Fluoxetine – First line for depression and anxiety – Used also to treat Panic disorder, generalized anxiety, obsessive-compulsive disorder, and posttraumatic stress disorder (PTSD). 35  2-Selective Inhibitors of Serotonin reuptake (SSRIs) Adverse effects: Because the SSRIs are more selective or serotonin reuptake than the TCAs at clinically effective doses, they have fewer adverse effects However, SSRI could cause sexual dysfunction and GI distress A more serious adverse effect of the SSRIs is serotonin syndrome, (elevation of 5-HT levels) occur when both an SSRI and an MAOI are administered concurrently. The clinical manifestations of serotonin syndrome include hyperthermia, muscle rigidity, myoclonus, and rapid fluctuations in mental status and vital signs. 36  3-Serotonin & NE reuptake inhibitors (SNRIs) – Block 5HT, and NE reuptake transporters in a concentration-dependent fashion – At low doses, they behave as SSRIs, but at higher doses, they also increase extracellular NE levels. – E.g. Venlafaxine Approved or the treatment of depression ( if patient does not respond to SSRI) as well as neuropathic pain and other pain syndromes. 37  4-NE-selective reuptake inhibitors (NRIs) Atomoxetine is an NE-selective reuptake inhibitor that is used in the treatment of ADHD. It is thought to improve ADHD symptoms by blocking NE reuptake, thereby increasing NE levels in the prefrontal cortex. Atomoxetine increases peripheral as well as central NE levels and thus increases heart rate and blood pressure. 38 Postulated mechanism of the delay in onset of the therapeutic effect of antidepressant medications. 39  Mechanism of antidepressant A.Before treatment, neurotransmitters are released at pathologically low levels and exert steady-state levels of autoinhibitory feedback. The net effect is an abnormally low baseline level of postsynaptic receptor activity (signaling). B. Short-term use of antidepressant medication results in increased release of neurotransmitters and/or increased duration of neurotransmitter action in the synaptic cleft. Both effects cause increased stimulation of inhibitory autoreceptors, with increased inhibition of neurotransmitter synthesis and increased inhibition of exocytosis. The net effect is to dampen the initial effect of the medication, and postsynaptic receptor activity remains at pretreatment levels. 40  Mechanism of antidepressant A.Chronic use of antidepressant medication results in desensitization of the presynaptic autoreceptors. Thus, the inhibition of neurotransmitter synthesis and exocytosis is reduced. The net effect is enhanced postsynaptic receptor activity, leading to a therapeutic response. 41 Serotonin Agonist & antagonist 42  1-Serotonin Receptor Agonists 5HT- receptor subtype specific agents used mainly for: – Anxiety – Migraine 5HT-1A selective partial agonist: Buspirone: Anxiolytic oAlthough it is often not as clinically effective as other anxiety treatments such as a benzodiazepine, buspirone is a useful option in some patients because it is nonaddictive, does not have abuse potential, and is nonsedating. 43  1- Serotonin Receptor Agonists (cont..) 5HT-1D and 5HT-1B agonist Effective in the treatment of migraine – By causing vasoconstriction – E.g triptans (general name for the drug class) – for acute migraine attack taken at the onset of an attack E.g. Sumatriptan 44  1-Serotonin Receptor Agonists (cont..) Tegaserod -5HT-4 agonists - Enhance GI motility - for constipation in IBS 45  2- Serotonin Receptor Antagonists Ondansetron – 5HT-3 antagonist – A potent anti-emetic (particularly through the (CTZ) chemoreceptor trigger zone.) Alosetron – 5HT-3 antagonists – Decreases serotonergic tone on intestines resulting in reduced GI motility – for diarrhea in IBS 46 Mood stabilizer 47  Monoamine hypothesis An excess of catecholamines (primarily NE an DA) can cause mania. Deficit of monoamines (primarily NE , DA and/or 5- HT) can cause depression. 48  Mood Stabilizer Lithium Lithium is a small monovalent cation It is similar in electrochemical properties to sodium and potassium. It has the potential to disrupt a number of proteins and transporters that require specific cation cofactors. Li+ is classified as a mood-stabilizing drug because it can reduce both manic and depressive symptoms of bipolar disorder. 49  Mood Stabilizer Lithium Mechanism of Action 1) Inositol signaling – Li+ inhibits inositol monophosphatase, the rate-limiting enzyme involved in inositol recycling. – By blocking the regeneration of PIP 2 , lithium decreases central adrenergic, muscarinic, and serotonergic neurotransmission. 50  Lithium phosphatase Inositol 1- Inositol 1- phosphatase phosphatase 51  Lithium 2. Increasing 5-HT neurotransmission by enhancing neurotransmitter synthesis and release 3. Decreasing NE and DA neurotransmission by inhibiting neurotransmitter synthesis, storage, release, and reuptake 4. Inhibiting adenylyl cyclase by decoupling G proteins from neurotransmitter receptors 5. Altering electrochemical gradients across cell membranes by substituting for Na+ and/or blocking K+ channels. 6. Recent studies indicate that lithium blocks glycogen synthase kinase 3 (GSK3) activity. GSK3 is a key enzyme in regulating the WNT signaling pathway, which controls adult neurogenesis and regulates multiple neuroplasticity mechanisms. 52  Summery TCAs, SSRIs, MAOIs, and other antidepressants have similar clinical efficacies when tested on groups of patients, although individual patients may respond to one drug and not to another. TCAs non-selectively inhibit 5-HT and NE reuptake transporters (in addition to other receptors); SSRIs selectively block 5-HT reuptake transporters; SNRIs selectively block 5-HT and NE reuptake transporters; MAOIs inhibit the degradation of both 5-HT and NE. 53  Summery The choice of antidepressant medication or an individual patient depends on the two goals of finding an effective agent for that patient and minimizing adverse effects. SSRIs have become the most commonly prescribed antidepressants because of their favorable therapeutic index and are the first-line pharmacologic choice or treatment of MDD, anxiety, obsessive compulsive disorder, and posttraumatic stress disorder. 54  Case Mary R is a 27-year-old office worker who presents to her primary care physician, Dr. Lee, with an 8-lb. weight loss over the previous 2 months. Ms. R tearfully explains that she is plagued by near-constant feelings of sadness and by a sense of helplessness and inadequacy at work. She feels so terrible that she has not had a good night of sleep in more than a month. She no longer enjoys living and has recently become scared when new thoughts of suicide enter her mind. Ms. R tells Dr. Lee that she had felt like this once before, but it had passed after several months. Dr. Lee asks her about her sleep patterns, appetite levels, ability to concentrate, energy level, mood, interest level, and feelings of guilt. He asks her specific questions about thoughts of suicide, particularly whether she has formed a specific plan and whether she has ever attempted suicide. Dr. Lee explains to Ms. R that she has major depressive disorder, likely caused by specific abnormalities in the function of her brain circuitry, and he prescribes the antidepressant fluoxetine. 55  Two weeks later, Ms. R calls to indicate that the medicine is not working. Dr. Lee encourages her to continue taking the medicine, and after 2 more weeks, Ms. R begins to feel better. She no longer feels sad and demoralized; the feelings of helplessness and inadequacy that previously plagued her have diminished. In fact, when she returns to see Dr. Lee 6 weeks later, she reports feeling much better. She no longer needs much sleep and is always full of energy. She is now convinced that she is the most intelligent person in her company. She proudly tells Dr. Lee that she has recently purchased a new sports car and gone on a large shopping spree. After taking a more detailed history, Dr. Lee tells Ms. R that she may be having a manic episode and, in consultation with a psychiatrist, prescribes lithium and gradually tapers the fluoxetine. Ms. R is hesitant to take the new medication, arguing that she feels fine and that she is concerned about the adverse effects of lithium. 56  Questions How is a depressive episode different from occasionally “feeling blue”? What caused Ms. R’s mania? Why is it necessary to treat bipolar disorder if the patient “feels good”? Why is there a delay in the onset of fluoxetine’s therapeutic effect? What specific concerns might Ms. R have about the adverse effects of lithium? 57  Which of the following adverse effect is most likely to occur when taking monoamine oxides inhibitor with cheese containing tyramine? A.Hypertension crisis B.Muscle pain C.Neurological disorder D.Nausea and vomiting 58  Which of the following drugs is an SSRI? A. Phenelzine B. Nefazodone C. Venlafaxine D.Citalopram 59  Identify side effects for each classification. A. TCA B. SNRI C. MAOI 60