This is an overview of drugs used to treat migraine with an emphasis on serotonergic drugs. This presentation was for 2nd year pharmacy students as part of a pharmacology & toxicology course and accompanies Goodman & Gilman's (12e) chapter 46. A bit of general background on 5-HT is also included.
Introduction to Physiological and pathological role of serotonin
Autocoids, Classification, synthesis ,Serotonergic receptors, Physiological actions, Pathophysiological role
Presented by
K.Firdous banu
Department of Pharmacology
learning objective includes : pathogenesis,clinical features, classification of migraine, pharmacology about specific antimigraine drugs, coverage to newer triptan- Lasmiditan and newer prophylactic drug Erenumab a CGRP receptor antagonist.
Overview of Discussion-
What is Serotonin?
Physiologic Distribution of Serotonin
Synthesis, Storage and Destruction
Biosynthesis of 5HT compared to CAs
Serotonin Uptake
5-HT Receptors
Actions
Pathophysiological Roles
Use
Drugs Affecting 5-HT System
Introduction to Physiological and pathological role of serotonin
Autocoids, Classification, synthesis ,Serotonergic receptors, Physiological actions, Pathophysiological role
Presented by
K.Firdous banu
Department of Pharmacology
learning objective includes : pathogenesis,clinical features, classification of migraine, pharmacology about specific antimigraine drugs, coverage to newer triptan- Lasmiditan and newer prophylactic drug Erenumab a CGRP receptor antagonist.
Overview of Discussion-
What is Serotonin?
Physiologic Distribution of Serotonin
Synthesis, Storage and Destruction
Biosynthesis of 5HT compared to CAs
Serotonin Uptake
5-HT Receptors
Actions
Pathophysiological Roles
Use
Drugs Affecting 5-HT System
This presentation is about the neurotransmitter 5-HT (serotonin), we focused on its definition, biosynthesis, storage and destruction, with mentioning its both central and peripheral effects, and lastly the serotonin receptors in the human body, as well as their agonist and antagonists.
Seretonin (5HT) and Its Antagonists PharmacologyPranatiChavan
Serotonin is a chemical that has a wide variety of functions in the human body. It is sometimes called the happy chemical, because it contributes to wellbeing and happiness.
The scientific name for serotonin is 5-hydroxytryptamine, or 5-HT. It is mainly found in the brain, bowels, and blood platelets.
Serotonin is used to transmit messages between nerve cells, it is thought to be active in constricting smooth muscles, and it contributes to wellbeing and happiness, among other things. As the precursor for melatonin, it helps regulate the body’s sleep-wake cycles and the internal clock.
It is thought to play a role in appetite, the emotions, and motor, cognitive, and autonomic functions. However, it is not known exactly if serotonin affects these directly, or if it has an overall role in co-ordinating the nervous system.
Serotonin is major neurotransmitter and affects the physiology of our body. Serotonin antagonists are used in various pathological conditions of body. This is a small presentation showing feature of serotonin.
This presentation impart a knowledge about Histamine,receptor,and antagonist.
Recent advances also mentioned like H3 & H4 receptors role in cognitive impairment etc.
This presentation is about the neurotransmitter 5-HT (serotonin), we focused on its definition, biosynthesis, storage and destruction, with mentioning its both central and peripheral effects, and lastly the serotonin receptors in the human body, as well as their agonist and antagonists.
Seretonin (5HT) and Its Antagonists PharmacologyPranatiChavan
Serotonin is a chemical that has a wide variety of functions in the human body. It is sometimes called the happy chemical, because it contributes to wellbeing and happiness.
The scientific name for serotonin is 5-hydroxytryptamine, or 5-HT. It is mainly found in the brain, bowels, and blood platelets.
Serotonin is used to transmit messages between nerve cells, it is thought to be active in constricting smooth muscles, and it contributes to wellbeing and happiness, among other things. As the precursor for melatonin, it helps regulate the body’s sleep-wake cycles and the internal clock.
It is thought to play a role in appetite, the emotions, and motor, cognitive, and autonomic functions. However, it is not known exactly if serotonin affects these directly, or if it has an overall role in co-ordinating the nervous system.
Serotonin is major neurotransmitter and affects the physiology of our body. Serotonin antagonists are used in various pathological conditions of body. This is a small presentation showing feature of serotonin.
This presentation impart a knowledge about Histamine,receptor,and antagonist.
Recent advances also mentioned like H3 & H4 receptors role in cognitive impairment etc.
Examination of Sexually Dimorphic Behavior on the Novel-Image Novel-Location ...Brian Piper
Objectives: Sex differences in object location memory favoring females appear to be a replicable phenomenon but may also depend on the task demands. This investigation evaluated if females outperformed males at both a short (immediate) and long (half-hour) interval between the learn and test condition using a recently developed version of the Novel-Image Novel-Location (NINL) test (Piper et al. 2011, Physiology & Behavior,
103, 513 - 522). Methods: Young-adults (N = 184) completed a standardized handedness inventory and the NINL. Results: Participants assigned to the Immediate and Delayed conditions did not differ in age, sex, or handedness. The NINL total score was higher among females at the Immediate, but not Delayed, interval. However, within the Delayed condition, females excelled at correctly identifying the unchanged items with a similar pattern for the Novel-Location (NL) scale. Conclusions: These findings are consistent with the view that sexually dimorphic performance favoring females in neurocognitive function can also extend to tasks that have a spatial component.
Lecture 24 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University.
Pharmacotherapies for neurodegenerative disordersBrian Piper
This seminar was presented to 2nd year pharmacy students enrolled in a pharmacology & toxicology course and accompanies Goodman & Gilman's (12e) chapter 22.
Lecture 6 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Includes neurotransmitter release, reuptake, and inactivation
Pharmacotherapies for parkinsons diseaseBrian Piper
This seminar was delivered to 2nd year pharmacy students as part of 2 lectures for a pharmacology & toxicology class. This material accompanies Goodman & Gilman's (12e) chapter 22.
Drug Abuse & Society (RX 462) Presentations-Spring 2014Brian Piper
This includes end of the semester presentations made by 2nd and 3rd year pharmacy students as part of an elective course. Each student was asked to provide information about history, epidemiology, pharmacodynamics, pharmacokinetics, and toxicology. Older "classic" (psilocybin, ayahuasca, crack), newer (JWB-018, mephedrone, MDA) drugs were covered as well as agents that have appreciable use outside the U.S. (desomorphine, areca nut, kava).
Overview of electronic cigarettes including history, components, safety and adverse events, efficacy in smoking cessation, pharmacokinetics and epidemiology. This presentation was originally delivered to 2nd year pharmacy students as part of a two semester class on pharmacology and toxicology.
Lecture 23 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Includes epidemiology, pharmacokinetics, of pharmacodynamics of LSD, ketamine, PCP, and peyote.
This lecture was delivered to 2nd year pharmacy students enrolled in a pharmacology & toxicology course. This presentation was designed to accompany Goodman & Gilman's (12e) chapter 12.
Lecture 20 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Focus is on the pharmacological treatment of depression.
Lecture 1 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Covers writing a research paper, routes of administration, writing a research paper, animal research ethics, neurochemistry.
This presentation was delivered over two days to second year pharmacy students enrolled in a course in pharmacology & toxicology. This lecture is designed to accompany Goodman & Gilman's (12e) chapter 11.
ppts on serotonins and pharmacotherapy of migraineSunandaMohan
In this PowerPoint discussed about the types of serotonins receptors. mechanism of action, pharmacological action, uses and adverse effects.
discussed about the agonist and antagonist drugs mode of action.Serotonin and Enteramine
Both are 5-Hydroxytryptamine (5-HT) – a monoamine neurotransmitter - derived from tryptophan.
Feelings of well-being
Present in GI cells (90%)
90% in E C cells and 10% in neurons of different plexuses.
10% in platelets and brain
Synthesis, Metabolism and Destruction
Dietary tryptophan
converted to 5–hydroxy– tryptophan by tryptophan hydroxylase
then to 5-HT by a non–specific decarboxylase
5 –HT is β-aminoethyl -5-Hydroxyindole
Degradation:
mainly monoamine oxidase (MAO–A > MAO–B)
5–hydroxyls Indole acetic acid (5-HIAA) in urine.
Platelets do not synthesize 5-HT (absence of tryptophan
hydroxylase) – takes up from intestinal blood vessels.
Stored in storage vesicles by active uptake – Vesicular.
monoamine transporter (VMAT2) – inhibited by Reserpine.
All are GPCRs except 5-HT3
Decrease cAMP production – 5-HT1
Increase cAMP production – 5-HT4, 5-HT6, 5-HT7.
Generating IP3/DAG – 5-HT2.
5-HT3 – Ligand gated Na+ K+.channel – faster depolarization.
HT1 A ,B, D , E, F - all are autoreceptors and inhibit firing of neurones or release of 5-HT – inhibit cAMP (Gi/Go)
5-HT1A – also activates K+ channel and inhibits Ca++ channel.
Somadendritic synapse in Raphe nucleus – Brainstem
and hippocampus (antianxiety – Buspirone)
5-HT1D – Basal ganglia and substantia nigra (dopeminergic).
5-HT1D/1B – Cranial Blood Vessels (for constriction – sumatriptan - agonist).
Also inhibits 5-HT release in forebrain and NA release in sympathetic nerve endings.
5-HT2: Gq type GPCR family – Phospholipase C – IP3/DAG
Mainly 3 subtypes (5-HT2A, B, C)
5-HT2 A - - also inhibits K+ channels
Located in all smooth muscles - vascular, visceral, platelets and cerebral neurones (prefrontal cortex)
Mediates direct effects of 5-HT (D-type)
Vasoconstriction, intestinal, uterine and bronchial constrictions, platelet aggregation and activation of cerebral neurons.
Ketanserin, Cyproheptadine, Methysergide are antagonists
5-HT2B – contraction of Rat gastric fundus.
5-HT2 C – Vascular endothelium – E D R F release (Vasodilatation) and C S F formation in choroid plexus.
Neuronal receptors – depolarizes rapidly by acting on Na+ K+ channel and also Ca++ channel
Mediates indirect and reflex actions.
Somatic and autonomic nerve endings – pain, itch, and coronary chemoreflex (bradycardia, fall in BP, respiratory stimulation/apnoea depending on stimulation of receptors in coronary bed).
Myenteric plexus – increased peristalsis and emetic reflex
Area postrema and NTS – vomiting and nausea.
Ondansetron in specific antagonist – C N S as well as peripheral action.
Gs type of receptor – activates adenylyl cyclase
Mucosa, plexuses and smooth muscles of Gut.
Augmentation of Intestinal secretion and peristalsis.
CTZ
Lecture 7 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University.
Autocoids are the self treating substance and local hormones . which is create changes in body Phisiology on the situation of to admine poisonous as well as foreign substance.
in this ppt gives Physiology of 5HT , Prostaglandin, and Histamine with their clinical use and adverse effect.
Also discussed about anti histamine , 5 HT antagonist with suitable examples.
A catecholamine is a monoamine, an organic compound that has a catechol (benzene with two hydroxyl side groups at carbons 1 and 2) and a side-chain amine. Included among catecholamines are epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine. Release of the hormones epinephrine and norepinephrine from the adrenal medulla of the adrenal glands is part of the fight-or-flight response.
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Current recreational drugs: RX462 Drug Abuse & Society, Spring 2015 Class pre...Brian Piper
These are the presentations from 2nd and 3rd year pharmacy students from semester long projects on a recreational drug of their choosing. Each presentations contains what was currently known (as of spring, 2015) about the history, epidemiology, pharmacokinetics, and pharmacodynamics of a recreational drug of their choosing.
Drug abuse and society drug presentations: Spring 2013Brian Piper
This presentation is on recreational drugs as part of a elective course for 2nd and 3rd year pharmacy students. The instructions were to include what is known about history, pharmacodynamics, pharmacokinetics including common routes of administration, overdose potential, and recent epidemiology.
The class chose some older agents (peyote, LSD, mushrooms, cocaine), others that have only become more popular recently (bath sats, synthetic cannabinoids), and some medical drugs (methylphenidate, oxycontin).
This is an overview of drugs used to control nausea and vomiting. This presentation was for 2nd year pharmacy students as part of a pharmacology & toxicology course and accompanies Goodman & Gilman's (12e) chapter 46.
3. Serotonin in Different Species
C. Elegans (roundworm) Betta splendens (Siamese fighting fish) lobster
C57 mouse Long-Evans rat marmoset
4. Biosynthesis: Tryptophan
• Essential amino acid
Food g tryptophan / 100 g food
salami 0.253
lentils 0.251
turkey (breast) 0.194
almonds 0.192
walnuts 0.17
asparagus 0.027
USDA National Nutrient Database for Standard Reference, Release 19 (2006).
5. Biosynthesis of 5-Hydroxytryptamine
• Tryptophan hydroxylase: found in axons, rate limiting
step
• L-aromatic amino acid decarboxylase (AACD): not rate
limiting step, also important for catecholamine
General Rule:
Depleting 5-HT: easy
Increasing 5-HT: not easy
6. Where is 5-Hydroxytryptamine
(Serotonin) localized?
• Enterochromaffin cells (90%)
• Platelets: thombosis
• Central nervous system (10%)
– Dorsal raphe: forebrain (lateral)
– Medial raphe: forebrain (medial)
– Nucleus raphe magnus: spinal
cord
Kranz et al. (2012). PNAS, 109(29), e2000.
7. 5-HT & Aggression
• Para-chlorophenylalanine (PCPA): irreversible
tryptophan hydroxylase inhibitor
• PCPA treated rats were tested for muricide
• Inverse relationship between 5-HT &
aggression
Killers Non-killers
Control 0 13
PCPA 14 4
Paxinos et al. (1977). Pharmacology, Biochemistry, Behavior, 6, 439-447.
8. Serotonin Transporter
• SERT removes 5-HT from synapse
• Localized at cleft, along axon, & on
soma
Stahl (2008). Essential Psychopharmacology. p. 93.
9. Serotonin Transporter (SERT) Reflects
Axon Integrity
• High dose 3,4-methylenedioxymethamphetamine (MDMA or
“ecstasy”) damages 5-HT axons
• SERT can be measured with immunocytochemistry
10. Serotonin fibers in the caudate nucleus of a control squirrel monkey
(A), a monkey that received 5 mg/kg MDMA 2 weeks (B), or 7 years
(C) previously.
Hatzidimitriou et al. (1999). Journal of Neuroscience, 19, 5096-5107.
11. Breakdown of 5-Hydroxytryptamine
Monoamine Oxidase (MAO): target of older
antidepressant drugs
5-HIAA: found in Cerebral Spinal Fluid
NADH: nicotine adenine dinucleotide, reduced;
increased by ethanol!
Sanders-Bush & Hazelwood (2012). In Pharmacological Basis of Therapeutics, p. 336.
12. Ergot Poisoning
• Fungus (Claviceps purpurea) found on grain contains
ergotamine
• Antiquity: Saint Anthony’s fire (convulsions & gangerine)
• Modern Case: Pont St. Espirit, France 1951
– Early Symptoms (6-48 hours): diffuse abdominal pain
(burning sensation throughout whole digestive tract),
nausea, vomiting, insomnia lasting several days
– Middle Symptoms ( ≈2 days – 1 week): cold extremities,
cramps of calves, logorrhea, visual hallucinations (themes =
animal & self-accusation)
– Late Symptoms (≈post 1 week): muscular spasm &
cardiovascular collapse (4 died)
Summarized from Gabbai et al. (1951). British Medical Journal, Sept 15, 650-651.
13. History of LSD
• Lysergic acid diethylamide was synthesized by Hoffman (1938)
from ergotamine
• CIA explored use (1950s)
• Counter-culture use (1960s) Albert Hoffman, Ph.D.
• 5-HT2A antagonist
• Schedule I
• Adjunct to psychotherapy?
1906 - 2008
14. History of LSD
• Lysergic acid diethylamide was synthesized by Hoffman (1938)
from ergotamine
• CIA explored use (1950s)
• Counter-culture use (1960s)
• 5-HT2A antagonist/5-HT1A agonist
• Schedule I
• Adjunct to psychotherapy?
1st 3 min: http://www.youtube.com/watch?v=HBOPFWmZCdM&list=LPNw1MNHLBky4&index=2&feature=plcp
15. 5-HT Receptor Tissue Post-Receptor Agonist (Ag) or
Mechanism Antagonist (Ant)
1A Raphe, hippocampus Gi Ag: 8-OH-DPAT
1B substantia nigra (SN) Gi Ag: Sumatriptan
1C (oops, 2C)
1D brain Gi Ag: Sumatriptan
1E cortex, putamen Gi
1F cortex, hippocampus Gi
1P enteric nervous system Go Ant: Ranzapride
2A platelets, smooth muscle Gq Ag: DOI; Ant: Ketanserin
2B stomach fundus Gq Ag: DOI
2C Hippocampus, SN Gq Ag: DOI
3 area postrema Na+ channel Ag: ondansetron
Based on Katzung et al. (2012). Basic & Clinical Pharmacology, p. 282.
16. 5-HT & Anxiety:
Light Dark Test
• Role of GABA or 5-HT in anxiety
--------------------------------- --------------------------------------------------
17. 5-HT & Depression
• Methods: 15 un-medicated women with a
history of 2+ episodes of depression were on a
low protein diet for 1 week, then randomly
assigned to receive:
– Tryptophan + : L-tryptophan (1.9 g), L-alanine (4.6
g) L-arginine (4.1 g)
– Tryptophan - : L-alanine (4.6 g) L-arginine (4.1 g)
Smith et al. (1997). Lancet, 349, 915-919.
21. Migraine Terminology
• migraineurs: person who experiences migraines
• aura: collection of symptoms that may precede or
co-occur; typically visual, lasts less than 1 hour
– positive features
• scintillations: a rapidly oscillating pattern of visual distortions
• photopsia: perception of flashes of light
• teichopsia: spot of flickering light
– negative features
• scotoma: an area of diminished vision within the visual field
• hemianopsia: blindness in half of the visual field, may involve
one or both eyes
– hemiplegic aura: occurring on one side of body
– basilar type aura: aura is localized to the brainstem
DiPiro et al. (2008). Pharmacotherapy: A Pathophysiologic Approach. p. 1008.
22. George Cruikshank: The Head Ache (1819)
2:20: http://www.mayoclinic.com/health/migraine-aura/MM00659
23. International Headache Society Migraine Criteria
• Migraine with aura (classic migraine)
– At least 2 attacks
– Aura fulfills criteria for typical aura, hemiplegic aura, or basilar
type aura
– Not attributed to another disorder
• Migraine without aura
– At least 5 attacks
– Headache lasts 4 to 72 hours (untreated or successfully treated)
– Headache has at least 2 characteristics
• Unilateral location, pulsating quality, or moderate or severe intensity
– Aggravation by or avoidance of routine physical activity
(walking, climbing stairs)
– During headache, at least one of the following:
• Nausea, vomiting, or both
• Photophobia and phonophobia
– Not attributed to another disorder
http://ihs-classification.org/en/02_klassifikation/02_teil1/01.00.00_migraine.html
25. Pathophysiology
• limited animal models
• theory: genetic (50% heritable) & neurovascular
• 2 min: http://www.youtube.com/watch?v=yZr9Joe85wg
• orthodromic: electrical potential following typical direction (soma
to axon)
• antidromic: electrical potential traveling in the reverse direction
(axon to soma)
26. Ergot Alkaloids
• Used for moderate to severe migraines (non-
prophylactic) but not other pain
• Vasoconstrictive agents with long history (1920s)
but dirty drugs (5-HT, dopamine, adrenergic)
27. Effects of ergot derivatives on contraction of isolated segments of human basilar artery strips
removed at surgery. All ergot derivatives are partial agonists, and all are more potent than
full agonists, norepinephrine (NE) and serotonin (5-HT). Dihydroergotamine (DHE), ergotamine
(ERG), methysergide (MS), and methylergometrine (MT).
Modified from Katzung (2012). Basic & Clinical Pharmacology. p. 289.
31. Triptans
• Recently developed (1990s) 5-HT1B/1D agonists act
on neurons & blood vessels
• First line therapy for moderate to severe
migraines (non-prophylactic)
• Should not be used with SSRI
32. Example Trial Evaluating Triptans
*
* *
Effects of sumatriptan (6 mg injected subcutaneously, N=734) or placebo (N=370) on symptoms
of acute migraine 60 minutes after subcutaneous injection. From Cady et al. (1991). JAMA, 265,
2831-2835.
35. Goodwin (13) & Related Terminology
Enterochromaffin cells (p. 335): a type of enteroendocrine cell occuring in the epithelia lining the
lumen of the digestive tract and the respiratory tract
tunicate (p. 335): marine filter feeders (image, lower right)
coelenterate (p. 335): outdated zoological term for 2 phyla including comb jellies (image, lower
left) and sea anemonies
psychotomimetic (p. 337): drug that mimics elements of mental illness (psychosis)
choroid plexus (p. 337): layer fo cells found in ventricles of brain that produce cerebral spinal fluid
superior colliculus (p. 340): Latin: upper hill , anatomical structure (image, middle, see arrow)
hyperacusis (p. 345): oversensitivity to certain frequencies of sound
paresthesias (p. 346): sensation of tingling or burning, aka “pins & needles”
asthenia (p. 346): weakness
precordial (p. 348): pertaining to the region over the heart/stomach
Horton’s syndome (p. 349): aka cluster headache, intense pain typically on one side of the head