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5-HT
Amine autacoid serotonin- in serum, on blood clotting Enteramine- in enterochromaffin cells of GIT- smooth muscle contraction 1950s- 5-HT: 5- HYDROXY TRYPTAMINE
5-HYDROXYTRYPTAMINE (SEROTONIN)
3-[beta-aminoethyl]-5-hydroxyindole)
widely distributed in the animal and plant kingdoms In vertebrates, tunicates, mollusks, arthropods, coelenterates, fruits-banana, pear, pineapple, tomato,,nuts. Venoms (e.g stinging nettle, wasps, and scorpions) In enterochromaffin cells throughout the gastrointestinal (GI) tract (90%) In storage granules in platelets Throughout the central nervous system (CNS)
Tryptophan, is actively transported into the brain by a carrier protein that also transports other large neutral and branched chain amino acids oxidase that requires O2 and a reduced pteridine cofactor, is the rate-limiting enzyme in the synthetic pathway. Tryptophan
PCPA
T .hydoxylase
5-hydroxytryptophan
5-HT .L decarboxylase
5-HTcontd
The enzyme that converts L-5-hydroxytryptophan to 5-HT, aromatic L-amino acid decarboxylase, is the same enzyme that decarboxylates L-dopa in catecholamine synthesis
Storage: in secretory granules by a vesicular transporter and released by exocytosis. Action terminated by Neuronal uptake mediated by a specific 5-HT transporter localized in the membrane of serotonergic axon terminals and in the membrane of platelets (where it takes up 5-HT from the blood). This uptake system is the only way that platelets acquire 5-HT (they lack the enzymes required to synthesize 5-HT).
5-HTcontd
Metabolism Oxidative deamination by MAO-A, with subsequent conversion of the aldehyde to 5-hydroxyindole acetic acid (5-HIAA) by an aldehyde Dehydrogenase Reduction of the acetaldehyde to an alcohol, 5hydroxytryptophol, is normally insignificant 5-HIAA LEVELS: Marker for carcinoid syndrome, providing a reliable diagnostic test for the disease actively transported out of the brain by a process that is sensitive to probenecid. Metabolite excreted in the urine
Another close relative of 5-HT, melatonin (5-methoxy-Nacetyltryptamine), is formed by sequential N-acetylation and O-methylation Melatonin is the principal indoleamine in the pineal gland, where it may be said to constitute a pigment of the imagination MAO-A preferentially metabolizes 5-HT and norepinephrine; clorgyline is a specific inhibitor of this enzyme. MAO-B prefers b-phenylethylamine and benzylamine as substrates; low dose selegiline is a relatively selective inhibitor of MAO-B. Dopamine and tryptamine are metabolized equally well by both isoforms. Neurons contain both isoforms of MAO, localized primarily in the outer membrane of mitochondria. MAO-B - isoform in platelets
IMPORTANT ones
5-HT1A, B, D: 5-HT2A: 5-HT3 5-HT4
autoreceptors- inhibit serotonergic activity in brain0 e g: Buspirone. Sumatriptan (agonist) platelets, vasc smth M, : Ketanserin(antagonist) emesis, peristalsis: secretion:
:prokinetic:
5-HT2 RECEPTORS
Distributed in: CNS, serotonergic terminal areas. High densities : prefrontal, parietal, and somatosensory cortex, claustrum, platelets. Originally were described in stomach fundus. The 3 subtypes : linked to phospholipase C with the generation of two second messengers, diacylglycerol (a cofactor in the activation of protein kinase C) and inositol trisphosphate ( mobilizes intracellular stores of Ca2+) 5-HT2B: Expression of receptor messenger RNA (mRNA) is highly restricted in the CNS. 5-HT2C: High density in the choroid plexus, an epithelial tissue that is the primary site of CSF production. 5-HT2C: Implicated in feeding behavior and susceptibility to seizure.
5-HT3 RECEPTORS Located on parasympathetic terminals in GI tract : vagal and splanchnic afferents; CNS: solitary tract nucleus and the area postrena The only monoamine neurotransmitter receptor A ligand-operated ion channel receptor. Activation elicits a rapidly desensitizing depolarization, mediated by the gating of cations. In GI tract and the CNS : participate in the emetic response, providing an anatomical basis for the antiemetic property of 5-HT3 receptor antagonists.
In CINV( Chemotherapy induced Nausea& Vomition)
5-HT4 RECEPTORS Widely distributed throughout the body. CNS: in neurons of the superior and inferior colliculi and in the hippocampus. GI tract: neurons of the myenteric plexus and on smooth muscle and secretory cells. Thought to evoke secretion in the alimentary tract and to facilitate the peristaltic reflex. Couple to Gs to activate adenylyl cyclase, leading to a rise in intracellular levels of cyclic AMP, possibly accounting for the utility of prokinetic in GI disorders
OTHER 5-HT RECEPTOR SUBTYPES 5-HT5A- receptor couples to inhibit adenylyl cyclase; 5-HT5B- Functional coupling of the cloned receptor has not been described. 5-HT6 and 5-HT7, are linked to activation of adenylyl cyclase. 5-HT7 receptors play a role in smooth-muscle relaxation in the GI tract and the vasculature. The atypical antipsychotic drug clozapine has a high affinity for 5-HT6 and 5-HT7 receptors
Enterochromaffin cells of the GI mucosa (highest density in the duodenum) synthesize and store 5-HT and other autacoids. Basal release of enteric 5-HT : Augmented by mechanical stretching and efferent vagal stimulation. An additional role in stimulating motility via the myenteric network of neurons ECF CELLS- enters the portal vein -metabolized by MAO-A (liver). 5-HT that survives hepatic oxidation is rapidly removed by the endothelium of lung capillaries and then inactivated by MAO.
ENTEROCHROMAFFIN TRACT.contd
CELLS
AND
GASTROINTESTINAL
nerve stimulation, increases in intraluminal pressure, and lowered pH, triggering peristaltic contraction.
5-HT released by mechanical or vagal stimulation also acts locally to regulate GI function. Motility of gastric and intestinal smooth muscle may be either enhanced or inhibited via at least six subtypes of 5-HT receptors
Abundant 5-HT3 receptors on vagal andother afferent neurons and on enterochromaffin cells play a pivotal role in emesis
PLATELETS Differ from other formed elements of blood in expressing mechanisms for uptake, storage, and endocytotic release of 5-HT Not synthesized in platelets, but is taken up from the circulation and stored in secretory granules by active transport, similar to the uptake and storage of NE by sympathetic nerve terminals A complex local interplay of multiple factors, including 5-HT, regulates thrombosis and hemostasis
When platelets contact injured endothelium, they release substances that promote platelet aggregation, and secondarily, they release 5-HT 5-HT binds to platelet 5-HT2A receptors and elicits a weak aggregation response that is markedly augmented by the presence of collagen. If the damaged blood vessel is injured to a depth where vascular smooth muscle is exposed, 5-HT exerts a direct vasoconstrictor effect, thereby contributing to hemostasis, which is enhanced by locally released autocoids (thromboxane A2, kinins, and vasoactive peptides). Conversely, 5-HT may stimulate production of NO and antagonize its own vasoconstrictor action (5-HT1 receptor), as well as the vasoconstriction produced by other locally released agents.
CARDIOVASCULAR SYSTEM
A variety of cardiac responses that result from activation of multiple 5-HT receptor subtypes, stimulation or inhibition of autonomic nerve activity, and reflex responses to 5-HT. On BP- IV: Triphasic response-early fall, brief rise follwoed by a prolonged fall Early Fall: due to stimulation of coronary chemoreceptors- BezoldJarisch Effect
Middle Pressor: vasoconstriction and increased card. Output Late Depressor: arteriolar dilatation and extravasation of fluids Heart : Weak Positive inotropic and chronotropic actions on the heart that may be blunted by simultaneous stimulation of
afferent nerves from baroreceptors and chemoreceptors.
CVScontd
Blood vessels:
sympathetic activity
Large vessels: (arteries and veins)-constriction by direct action of 5-HT( via 5-HT2A)- :Contraction, particularly in the splanchnic, Renal, pulmonary, and cerebral vasculatures. Arterioles and VSM: inhibitory(dilatory) , the result of stimulated NO and prostaglandin synthesis and blockade of NE release from sympathetic nerves. Constricts venules, increased capillary pressure and escaping of fluid from capillaries 5-HT amplifies the local constrictor actions of NE, and Ang II
CENTRAL NERVOUS SYSTEM A multitude of brain functions : Sleep, cognition, sensory perception, motor activity, temperature regulation, nociception, mood, appetite, sexual behavior, and hormone secretion. The principal cell bodies of 5-HT neurons: in raphe nuclei of the brainstem , project throughout the brain and spinal cord. In addition to being released at discrete synapses,5-HT released at nonsynaptic varicosities ( axonal swelling, termed varicosities) act as a neuromodulator as well as a neurotransmitter Newly formed 5-HT (Nerve terminals contain all of the proteins needed to synthesize 5-HT from L-tryptophan) is rapidly accumulated in synaptic vesicles, where it is protected from MAO. 5-HT released by nerve-impulse flow is reaccumulated into the presynaptic terminal by the 5-HT transporter
Respiratory system
Small direct stimulant effect on bronchiolar smooth muscle in normal humans. Facilitate acetylcholine release from bronchial vagal nerve endings. In patients with carcinoid syndrome, episodes of bronchoconstriction occur in response to elevated levels of the amine or peptides released from the tumor. May also cause hyperventilation as a result of the chemoreceptor reflex or stimulation of bronchial sensory nerve endings
Smooth muscles:
GIT: increase in GIT motility (5-HT2A-intestine, 5-HT 2B-gastric fundus, 5-HT 4-enetric fundus, 5-HT3enetric plexuses) Release augmented by: stretching(food), vagal stim., lowered pH Contraction of uterine Sm.M- Not much significant
Skeletal Muscle
5-HT2 receptors are present on skeletal muscle membranes, but their physiologic role is not understood. Malignant hyperthermia : a condition precipitated by certain anesthetic and neuromuscular agents that results in severe hyperthermia due to skeletal muscle overactivity and metabolic and autonomic instability. In a genetic porcine model of this condition, administration of serotonin or serotonin agonists can precipitate a typical attack. 5-HT2 blockers such as ketanserin can reduce or prevent many manifestations of the condition when evoked in this way. However, malignant hyperthermia provoked by anesthetic agents in these animals is not effectively prevented by 5HT2 antagonists. Serotonin syndrome: similar, ut not identical condition precipitated when MAO inhibitors are given with serotonin agonists, especially antidepressants of the selective serotonin reuptake inhibitor class (SSRIs).
DRUGS AFFECTING ACTION OF 5-HT 5-HT RECEPTOR AGONISTS: Selective- Azapirones, Triptans, Cisparide,Renzapride Non selective- LSD, Metoclopramide 5-HT RECEPTOR ANTAGONISTS: Selective- Ketanserin, ritanserin, Risperidone, Ondansetron Non selective- Ergot alkaloids, cyproheptadine
Triptans: MOA
Two hypotheses Constricts intracranial blood vessels, including arteriovenous anastomoses, and restores blood flow to the brain. may block the release of proinflammatory neuropeptides at the level of the nerve terminal in the perivascular space.
D-Lysergic Acid Diethylamide (LSD) Nonselective 5-HT agonist. Psychedelics (LSD) and other psychotomimetics: mescaline and psilocybin can induce states of altered awareness, or induce hallucinations and anxiety, probably mediated by 5-HT2A receptors. Profoundly alters human behavior, eliciting perception disturbances such as sensory distortion (especially visual and auditory) and hallucinations at low doses ( 1 mg/kg) Overactivity of these receptors: a role in the genesis of negative symptoms in schizophrenia and sleep disturbances Abuse by human beings and the fascination of scientists with the mechanism of action of LSD. LSD interacts with brain 5-HT receptors as an agonist/partial agonist. LSD mimics 5-HT at 5-HT1A autoreceptors on raphe cell bodies, partial or full agonists at 5-HT2A and 5-HT2C receptors.
Use of Ergot Alkaloids in Postpartum Hemorrhage All natural ergot alkaloids markedly increase the motor activity of the uterus. -contractions become more forceful and prolonged, resting tone is dramatically increased, and sustained contracture can result. This precludes their use for induction or facilitation of labor Compatible with the use postpartum or after abortion to control bleeding and maintain uterine contraction. primarily to prevent postpartum hemorrhage. Ergonovine (ergometrine) is the most active and also is less toxic than ergotamine. Methylergonovine ( & methyl ergometrine) - Uterinestimulating agents in obstetrics.
Ergot alkaloids: Contraindications: pregnancy, patients with peripheral vascular disease, coronary artery disease, hypertension, impaired hepatic or renal function, and sepsis. Ergot alkaloids should not be taken within 24 hours of the use of the triptans, and should not be used concurrently with other drugs that can cause vasoconstriction. Adverse Effects Nausea and vomiting, Leg weakness is common; muscle pains, occasionally severe,may occur in the extremities, as well as numbness and tingling of extremities.
Bromocriptine
is extremely effective in reducing the high levels of prolactin that result from pituitary tumors and has even been associated with regression of the tumor in some cases. Cabergoline is similar but more potent. Pseudopregnancy in bitches
Ketanserin and Ritanserin Potently blocks 5-HT2A receptors, less potently blocks 5HT2C receptors, and has no significant effect on 5-HT3 or 5HT4 receptors or any members of the 5-HT1 receptor family. Also has high affinity for a adrenergic and histamine H1 receptors. Lowers blood pressure in patients with hypertension, causing a reduction comparable to that seen with b adrenergicreceptor antagonists or diuretics. This effect likely relates to its blockade of alpha 1 adrenergic receptors, not its blockade of 5-HT2A receptors. Inhibits 5-HT-induced platelet aggregation but does not greatly reduce the capacity of other agents to cause aggregation. treatment of bloat in ruminants
Methysergide A congener of methylergonovine. Blocks 5-HT2A and 5-HT2C receptors but has partial agonist activity in some preparations. Inhibits the vasoconstrictor and pressor effects of 5-HT, as well as the actions of 5-HT on various types of extravascular smooth muscle. It can both block and mimic the central effects of 5HT. Not selective: it also interacts with 5-HT1 receptors Therapeutic effects appear primarily to reflect blockade of 5-HT2 receptors. Weak vasoconstrictor and oxytocic activity. Used for the prophylactic treatment of migraine
Cyproheptadine The structure resembles that of the phenothiazine histamine H1 receptor antagonists An effective H1 receptor antagonist. Also Prominent 5-HT blocking activity on smooth muscle via its binding to 5-HT2A receptors. I In addition: Weak anticholinergic activity, mild CNS depressant Effective in controlling skin allergies, the accompanying pruritus. Appetite stimulant: The 5-HT blocking actions of cyproheptadine: value in the postgastrectomy dumping syndrome, GI hypermotility of carcinoid syndrome, and migraine prophylaxis. Not, however, a preferred treatment for these conditions. Side effects : drowsiness. weight gain and increased growth
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