5-HT Agonists and Antagonists LECTURE NOTES PDF

Not for sale!! 5-HYDROXYTRYPTAMINE (5-HT) AGONISTS AND ANTAGONISTS S. O. OKPO, PhD DEPARTMENT OF PHARMACOLOGY AND TOXICOLOGY FACULTY O...

Not for sale!! 5-HYDROXYTRYPTAMINE (5-HT) AGONISTS AND ANTAGONISTS S. O. OKPO, PhD DEPARTMENT OF PHARMACOLOGY AND TOXICOLOGY FACULTY OF PHARMACY, UNIVERSITY OF BENIN, BENIN CITY. 5-hydroxytryptamine{3(β-aminoethyl) 5-hydroxyindole} is a very ubiquitous natural product found in plants, invertebrates and vertebrates. In man, it is found in many organs as well as blood, lymph and cerebrospinal fluid. It modulates the function of neurons and other cells but it is not essential for life. 5-HT found in diet is absorbed but contributes virtually nothing to tissue levels (except platelets, where it is taken up from the circulation) due to metabolism in the lungs and liver. Synthesis 5-HT is synthesized de novo from the essential amino acid tryptophan (primarily in serotonergic neurons and enterochromaffin cells in the intestine). L-Tryptophan Tryptophan hydroxylase (Rate limiting enzyme) L-5-hydroxy tryptophan 5-hydroxy tryptophan decarboxylase 5-hydroxytryptamine (5-HT) N-acetylase Monoamine oxidase (MAO) (MAO-A preferentially metabolizes 5-HT & NA) N-acetyl 5-HT Hydroxyindole o-methyl transferase Melatonin 5-OH indole acetaldehyde (maintenance of circadian rhythms and normal sleep-wake cycle) aldehyde dehydrogenase aldehyde reductase 5-OH indole acetic acid 5-OH tryptophol (5-HIAA) (Insignificant) Excreted in the urine. High amounts are excreted by patients with malignant carcinoid, so it is a diagnostic test for the disease Fig. 1: Synthesis and Metabolism of 5-HT 5-HT agonists and antagonists Page 1 of 9 Not for sale!! Other means of metabolism of 5-HT include:  Portal circulation to liver (first pass effect)  Uptake into lung epithelial cells  Accumulation into platelets (slowly) Distribution Serotonin is found in many tissues such as: GIT:- Contains about 95% of the total amount of serotonin of the body, localized in enterochromaffin cells. CNS:- Higher concentrations are found in brainstem than in cortex. Serotonin, released by presynaptic serotonergic neurons in synaptic clefts, activates specific receptors and is partly taken up by presynaptic neurons. Platelets - Practically all the serotonin in blood is found in platelets which do not synthesize it, but take it from plasma where it is released by enterochromaffin cells of the GIT. The uptake of serotonin by platelets is very fast. The half-life of serotonin in platelets is the same as that of platelets, i.e. five or six days. Serotonin released from platelets in plasma has a relatively localized effect on the vessels where it is released, for example during migraine. The half-life of serotonin is long in platelets and intestine, and very short, a few minutes, in the brain. Serotonin receptors 5-HT produces its effects through a variety of membrane-bound receptors. 5-HT and its receptors are found both in the central and peripheral nervous system, as well as in a number of non-neuronal tissues in the gastrointestinal tract, cardiovascular system and blood. 5-HT receptors are classified into 7 types and several are divided into subtypes. They are 5- HT1 (5-HT1A,B,D,E and F), 5-HT2 (5-HT2A,B,C), 5-HT3, 5-HT4, 5-HT5 (5-HT5A and B), 5-HT6 and 5-HT7. The majority of 5-HT receptors are postsynaptic but receptors such as 5-HT1A and 5- HT1B are mainly presynaptic and modulate serotonin release. With the exception of 5-HT3 receptor which is a ligand gated ion channel that gates Na+ and K+ (similar to the nicotinic receptor), all others belong to the super family of 7- transmembrane G-protein coupled receptors. 5-HT agonists and antagonists Page 2 of 9 Not for sale!! Pharmacological Actions Cardiovascular system The cardiovascular effects of serotonin are complex. They are variable depending on the dose injected, experimental conditions, animal species and vascular state. Blood vessels: Serotonin induces a vasoconstriction (direct 5-HT2 effect), particularly of renal vessels, or a vasodilation (an indirect effect mediated by NO or PGI2). Serotonin constricts veins and seems to induce venous thromboses and promotes platelet aggregating effect. It also increases capillary permeability. Heart: Serotonin has a positive chronotropic action by 5-HT4 receptor stimulation and could be involved in the genesis of certain rhythm disorders. It also has a positive inotropic effect. Blood pressure: Stimulation of sensory nerve endings in baroreceptors and in vagal afferents in coronary circulation elicits the Bezold Jarisch reflex causing intense bradycardia and hypotension. 5-HT also amplifies the local constrictor actions of noradrenaline, angiotensin II and histamine. Smooth muscles 5-HT induces contractions of intestine, bronchi and uterus. Small intestine: Serotonin increases intestinal motility, probably by stimulation of 5-HT4 and 5-HT3 receptors. This effect explains diarrhea observed in patients with carcinoid syndrome.Serotonin has an emetic effect by stimulation of 5-HT3 receptors located on the vagal terminations in the digestive tract and in area postrema (chemoreceptor trigger zone), which is accessible to peripheral circulating serotonin. Their stimulation elicits nausea and vomiting, and 5-HT3 antagonists are used to avoid vomiting induced by antineoplastic treatments. Administration of high doses of serotonin to animals induces gastric ulcerations. Bronchi: 5-HT has a bronchoconstrictive action in asthmatic airways. This is by stimulation of aortic and carotid chemoreceptors which leads to increased respiratory rate and minute volume. A serotonin aerosol induces dyspnea. Uterus: 5-HT induces contractions of the uterus. Serotonin is involved in allergic and inflammatory symptoms and in certain diseases such as: 5-HT agonists and antagonists Page 3 of 9 Not for sale!!  Carcinoid syndrome: This is caused by metastatic tumors of enterochromaffin cells of the GIT which secrete various compounds, in particular a large quantity of serotonin. It is characterized by diarrhea, flushes, dyspnea and sometimes damage to cardiac valves. The diagnosis of these tumors is based on the increase in serotonin concentration in blood and on the excretion of abnormal amounts of 5-hydroxy-indolacetic acid, 5- HIAA, in urine.  Migraine: Migraine is a disease characterized by repeated headache in which vasomotor phenomena and serotonin play a determining part. In the first prodromic phase, there is a vasoconstriction, and in the second painful phase, a vasodilation. This vasodilation is reduced by drugs which cause vasoconstriction.  Myocardial ischemia: Serotonin released from platelets seems to worsen the myocardial ischemia by vasoconstriction. Central effects Effects of serotonin on the CNS are numerous and complex. It is involved in the regulation of sleep, mood (antidepressant action), temperature, appetite (appetite suppressant effect). Overstimulation of 5-HT2 receptors can also induce positive and negative symptoms of psychotic disorders. Lysergic acid diethylamide (LSD), agonist of 5-HT2 receptors and also of D1 and D2 dopaminergic receptors, has hallucinogenic properties. Serotonin, due to its various types of presynaptic and postsynaptic receptors, modulates the activity of other transmitters. It plays a determining part in adaptation. Pathophysiological Roles of 5-HT and their Pharmacological Interventions 5-HT has been implicated in the aetiology of numerous disease states, including depression, anxiety, social phobia, schizophrenia, obsessive-compulsive and panic disorders; in addition to migraine, hypertension, pulmonary hypertension, eating disorders, irritable bowel syndrome and vomiting. Unlike noradrenaline or dopamine, 5-HT itself has no clinical uses However, its agonists and antagonists have very important therapeutic applications. Unlike histamine where only its antagonists are used, serotonin agonists and antagonists can be used for treatment of these disease states. 5-HT agonists and antagonists Page 4 of 9 Not for sale!! Migraine Migraine is a neurological condition characterized by a spectrum of signs and symptoms involving several organ systems. The syndrome may include aura of flashing lights, a throbbing unilateral headache, photophobia, hemianopia (loss of sight in half of the visual field), vomiting, polyuria, diarrhoea and disturbances of mood and appetite. It may result from cerebral vasoconstriction for the initial phase and vasodilation for the headache phase. Fig. 2: Pathogenesis of migraine and drug treatment The Ergot alkaloids and the Triptans (used to treat moderate to severe migraine attacks) are believed to act as agonists at one or more subtypes of the 5-HT receptor. The Triptans (sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan and almotriptan)  may cause cranial arterioles to constrict, reversing the abnormal dilatation that occurs in migraine.  may also activate neuronal presynaptic receptors thereby blocking the release of substance P into the perivascular space thereby reducing the signs and symptoms of migraine.  are much more selective agents than ergot alkaloids because they interact potently with 5-HT1D and 5-HT1B receptors and have low or no affinity for other subtypes of 5-HT 5-HT agonists and antagonists Page 5 of 9 Not for sale!! receptors. They are inactive at α1 and α2 adrenoceptors, β-adrenoceptors, dopaminergic, muscarinic and benzodiazepine receptors. Mild migraine attacks are treated with aspirin, acetaminophen, ibuprofen, ergotamine + caffeine (Cafergot®). Prophylaxis of severe migraine is by the use of Methysergide, a non-selective 5-HT agonist-antagonist which blocks 5HT2A and 5-HT2C receptors but has partial agonist activity in some preparations. Methysergide inhibits the vasoconstrictor effects of 5-HT as well as the actions of 5-HT on various types of extravascular smooth muscle. Since it is not selective, it also interacts with 5-HT1 receptors but its therapeutic effects appear primarily to be blockade of 5-HT2 receptors. Anxiety The mainstay of treatment for anxiety is still benzodiazepenes (BZPs). The 5-HT1A agonists are clinically used for treatment of anxiety. The prototype is Buspirone and others include Gepirone, Ipsapirone and Flesinoxan. They act by reducing 5-HT neurotransmission in the brain. However, they possess advantages over benzodiazepenes as anxiolytics because they lack sedation and dependence liabilities of BZPs. Depression Decrease in 5-HT neurotransmission, in particular brain areas, is associated with clinical depression. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetin act by blocking the 5-HT membrane transporter (uptake-1) thereby providing a higher concentration of 5- HT at the synapse and are now widely used as antidepressants. Other uses of SSRIs are in obesity, panic disorders, premenstrual syndrome, diabetic neuropathy, chronic pain and Alzheimer’s disease. Schizophrenia Atypical antipsychotics e.g., clozapine, risperidone and olanzapine which are potent D2 receptor antagonists also block 5HT2 receptors. Blockade of 5HT2 receptors may relieve the negative symptoms in schizophrenia (such as diminished speech, blunted emotions, loss of energy, anhedonia). This differs from effects of the typical antipsychotics which are more selective for dopamine receptors. The atypical antipsychotics produce minimal, if any, tardive dyskinesia. 5-HT agonists and antagonists Page 6 of 9 Not for sale!! Eating disorders 5HT plays a role in eating disorders. Therefore, agents that increase 5HT transmission such as SSRIs and fenfluramine induce weight loss by suppressing appetite, effects believed to occur in the hypothalamus though peripheral receptors in the GIT may be involved. 5HT receptor antagonists The 5-HT receptor antagonists used clinically and their applications are shown on the chart in Fig. 3. 5-HT receptor antagonists 5HT2A/2C 5HT3 Ketanserin Methysergide Atypical Ondansetron antipsychotics/ Palonosetron antidepressants Clozapine Agomelatine (Antidepressant) Fig. 3: 5-HT receptor antagonists 5HT3 antagonists are used in the treatment of emesis associated with cancer chemotherapy. Ondansetron, granisetron, palonosetron etc are selective antagonists for 5HT3 receptors particularly useful in the treatment of chemotherapy induced nausea and vomiting (CINV). It is believed that cancer chemotherapy causes the release of 5-HT from enterochromaffin cells of the small intestine hence the need for 5HT3 antagonists. 5-HT2 antagonists Ketanserin is a 5-HT2A/2C antagonist used for the treatment of hypertension. In addition to its serotonin antagonism, it has affinity for α1 adrenoceptors, which may contribute to its antihypertensive effect. Clozapine is an atypical antipsychotic drug that acts as 5-HT2A/2C receptor antagonist with high affinity for dopamine receptors. It represents a class of atypical antipsychotic drugs, one key advantage of this group is its reduced incidence of extrapyramidal side effects compared 5-HT agonists and antagonists Page 7 of 9 Not for sale!! to the classical antipsychotics, and possibly a greater efficacy for reducing negative symptoms of schizophrenia. Agomelatine is a new antidepressant with agonist action at the melatonin receptor and antagonism at the 5-HT2C receptor. 5-HT receptor agonists The agonists at the 5-HT receptors can be divided into two, namely: selective and non- selective (Fig. 4) 5-HT receptor agonists Selective Non- selective 5-HT1A 5-HT1B and 5-HT2 5-HT4 Ergotamine LSD 5-HT1D agonist agonists agonist agonist AZAPIRONES TRIPTANS TRAZODONE CISAPRIDE Buspirone Sumatriptan Gepirone Fig. 4: 5-HT receptor agonists Selective agonists 5-HT1A agonists Buspirone - a partial 5-HT1A agonist used clinically for the treatment of anxiety and depression. 5-HT1B and 5-HT1D agonists The “triptans” are a drug class useful for the treatment of acute migraine headaches. They act by binding to 5-HT1B and 5-HT1D receptors in cranial vessels, which leads to vasoconstriction and decreased release of neuropeptides involved in “sterile inflammation”. 5-HT2C agonist Trazodone was previously believed to be a 5-HT2C receptor antagonist. However, recent publications report that trazodone would behave as a 5-HT2C agonist. This drug is used generally as somnorific. 5-HT agonists and antagonists Page 8 of 9 Not for sale!! 5-HT4 agonists Cisapride is a serotonin and cholinergic agonist used as a prokinetic drug; it was withdrawn from the U.S. market because of cardiovascular toxicity. Selective serotonin uptake inhibitors, such as Fluoxetine, are used for depression and other indications (Fig. 5) Non-selective agonists Ergotamine activates a more than one subtype of 5-HT receptor, it binds to 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors. Its vasoconstrictor effect makes it a suitable treatment for migraine attacks. LSD is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist that has psychedelic properties. 5-HT Presynaptic agents Degradation Storage Reuptake Inhibitors Inhibitors Inhibitors MAO inhibitors Amphetamine SNRIs SSRIs TCAs Phenelzine Methylphenidate Venlafaxine Fluoxetine Imipramine Selegiline Modafinil Duloxetin Sertraline Desipramine Fig. 5: 5-HT inhibitors used clinically Table 1: Summary of the primary actions and clinical uses of serotonergic drugs RECEPTOR ACTION DRUG EXAMPLES CLINICAL DISORDER 5-HTIA Partial agonist Buspirone, ipsaperone Anxiety, depression 5-HTID Agonist Sumatriptan Migraine 5-HT2A/2C Antagonist Methysergide, trazodone, Migraine, depression, schizophrenia risperidone, ketanserin 5-HT3 Antagonist Ondasetron Chemotherapy-induced emesis 5-HT4 Agonist Cisapride Gastrointestinal disorders 5-HT transporter Inhibitor Fluoxetine, sertraline Depression, obsessive-compulsive disorder, panic disorder, social phobia, post-traumatic stress disorder. 5-HT agonists and antagonists Page 9 of 9