4. Roles of Dopamine
•Role in movement
•Role in pleasure and
motivation
•Controls the flow of
information from other
areas of the brain
5. Dopamine Receptors
•There are five types of dopamine receptors.D1,D2,D3,D4,D5.
•We can categorize dopamine receptors in two main subtypes:
•D1 like receptor family: the Gs protein is involved and adenylyl
cyclase would be activated. The action of the enzyme causes the
conversion of adenosine triphosphate to cyclic adenosine
monophosphate (cAMP).
•D2 like receptor family: which is the receptor combining with the
Gi protein and its activated alpha-subunit then inhibits adenylyl
cyclase so that the concentration of cAMP is reduced.
6. Effectors Pathways Associated
with G-Protein-Coupled
DOPA MINE
Efficacy
Receptors D1-D5
• PN08060.JPG
D2-D3-D4
Dr. Mejía 2004
Ziprasidone binds with high affinity to D2 receptors (Ki=3.1nM), (Ki=7.2 nM) to the D3, moderate
affinity (Ki=32 nM) to D4,
Low affinity (Ki=130 nM) to the D1 and D5
7. Dopamine Receptors
•Five subtypes of dopamine receptor have been cloned.
TheD1 andD5 receptors are closely related, and couple toGs
Alpha and stimulate adenylylcyclase activity. In contrast,
theD2, D3 andD4 receptors couple to Gi
Alpha and inhibit the formation of cAMP.
8. • D1 receptors
D Most abundant receptor in the central nervous
system
s Highly expressed in basal ganglia
H Stimulate AC
9. D5
•50% homology with D1
•Expression in nucleus of thalamus ;suggesting that role in
pain stimuli
•Stimulate AC
10. D2
•Inhibti AC, phospoinositide turnover
•Activation of potassium channel potentiation of
arachidonic acid release
Two isoforms;D2L and D2s by alternative splicing.
•Similar profiles in terms of affinity but different in
regulation.
•Highly expressed in basal ganglia, septi, ventral
tegmental area
11. D3
•As a functional receptor remains uncertain
•Similarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory
influences on production of neurotension.
12. D4
•Homology with D2 and D3 41% and 39%
•Hippocampus and frontal cerebral cortex
14. Therapeutic uses of DA1 Receptor Agonists
•Decreases peripheral resistance
•Inducing lowering of arteriel blood pressure-increases in
heart rate and increases in sympathetic tone
•Increases in activity of the reninaldosterone system
16. Theraputicuses of DA2 receptor
agonists
•Used for treating Parkinson’s
disease
•Inhibits prolactin release (which
decreases tumor size)
17. DA 1 Receptor Antagonists
•Clozapine( used for treating schizophrenia
18. SEROTONIN RECEPTORS
Introduction
Definition
Chemistry of serotonin and synthesis
Pharmacokinetics
Receptors classification
Mechanism of action
Pharmacological actions
Specific agonists and antagonists
19. INTRODUCTION
5-HT is an amine autocoid.
The Autocoid is derived from a Greek word; where, autos
means self and akos means healing or remedy or
medicinal substance. These autacoids are substances
that are produced in a wide variety of cells in the body
and they have widely differing structures &
pharmacological activities.
20. They generally act on the tissues which produce them at the
site of synthesis & are hence called as local hormones.
Prostaglandins, histamines & serotonin belongs to the group of
autocoids. Serotonin was the name given to a vasoconstrictor
substance found in the serum when blood clotted. It was
chemically identified as 5- hydroxytryptamine. It was found in
GIT and CNS, and was observed to be functioning as a
neurotransmitter and as local hormone in peripheral vascular
system.
21. Chemistry and Synthesis :
Serotonin is synthesized in biologic systems from the amino
acids L- TRYPTOPHAN by HYDROXYLATION of Indole ring.
After synthesis, the free amines undergoes inactivation by the
action of MAO (Mono Amine Oxidase).
22. 2. 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A, B, D,E,F . And
are distinguished based on their distribution and pharmacological
specificity. All subtypes of 5-HT1 receptors inhibits adenyl cyclase
These receptors are related to mood and behavior, migraine and
used to treat acute attacks. Moreover they activates potassium
channels and inhibits calcium channels. 5-HT1D receptors inhibit
noradrenaline.
2. 5-HT2 RECEPTOR :
There are 3 subtypes A, B and C. These are linked to phospholipase C .
It has peripheral effects on smooth muscles and platelets which are
mediated by 5-HT2A receptors. 5-HT2C receptor present on
endothelium produces vasodilation.
23. 3. 5-HT3 RECEPTOR These occur mainly in the peripheral nervous
system, mainly on autonomic and enteric neurons. These are of 2
types 5HT3A & 5HT3B These receptors have reflex effects on:
Somatic and autonomic nerve endings; shows pain, itch and other
visceral effects. Nerve endings in myenteric plexus; increase of
peristalsis, emetic reflex. Region of medulla; nausea, vomiting.
4. 5-HT4 RECEPTOR These are present in brain and peripheral
organs such as GIT, bladder and heart. In GIT they produces
neuronal excitation and mediate the effect of 5-HT in stimulating
peristalsis Ex; Cisapride, Renzapride.
24. PHARMACOLOGICAL ACTIONS
Cardiovascular system: Arteries are constricted (by the action
on smooth muscles) as well as dilated (through EDRF release)
In microcirculation 5HT dilates the arterioles and constricts
venules. Smooth muscles: 5-HT is a potent stimulation of g.i.t.,
both by direct action as well as through enteric plexus.
Peristalsis is increased and diarrhoea can occur.
25. 5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS:
Methysergide Pharmacological effects On central nervous
system it exerts mild CNS stimulation. On smooth muscles it
shows vasoconstriction and oxytocic effect. In migraine it is
used only as a prophylactic agent. MOA It stimulates the
receptors located in the brain. Adverse effects such as :
Nausea, vertigo, drowsiness. G.I.irritation, bradycardia,
insomnia.
26. THERAPEUTIC USES: It is used as a prophylactic agent in
migraine. Other antagonist drugs are: Pizofen It shows
antihistaminic and antidepressant effect Causes drowsiness,
urine retention and weight gain. Clozapine It is antipsychotic
agent which is dopaminergic antagonist as blocks 5-HT2A
and 5-HT2C receptors.
27. 2. 5-HT2A ANTAGONIST :
Ketanserin It is the prototype for the drugs having 5-HT2
receptor blocking activity. It produces antihypertensive activity.
It acts on platelets and prevents its aggregation. It also causes
bronchocostriction. Adverse effects are nausea, dryness of
mouth, tiredness. Clinical use: as a prophylactic agent in
Reynaud's disease. Cyproheptadine. It has anticholinergic and
ca2+ channel blocking effect. It shows mild CNS depressant
activity and causes sedation. It improves appetite by acting on
hypothalamus. Used in curing Cushing’s syndrome and
allergies.
28. • 5-HT3 ANTAGONISTS
• Ondansetron It is a prototype drug for antiemetic activity which was
developed to control emesis induced by cancer therapy and
radiotherapy. It acts by blocking the depolarizing action of 5-HT on
the 5-HT3 receptors located in brain. Adverse effects are headache,
constipation, diarrhoea, abdomen pain etc. Used as prophylaxis and
postoperative nausea and vomiting. Granisetron It is 15 times more
potent than Ondansetron. It is similar to Ondansetron. Adverse
effects fever, dizziness, anxiety etc.
•
29. OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine: it inhibits the enzyme tryptophan
hydroxylase and reduces the levels of HT.
Tricyclic antidepressants: inhibit 5-HT uptake along with
noradrenaline.
Reserpine: blocks the uptake of 5-HT into storage
granules.
Ergot alkaloids: they exert their effect through 5-HT,
adrenoreceptors or dopamine receptors. Clinically they
are used in treatment of attacks of migraine Also used to
treat carcinoid tumors. Adverse effects are muscle
cramps, weakness, nausea, vomiting etc
31. Mechanism of Action of Antipsychotic Drugs
Dopaminergic Pathways
Goals: Presynaptic
Dopaminergic Neuron
To quiet hyperactive DA
neurons that mediate
psychosis
Autoreceptor
To trigger underactive DA
neurons that mediate Antipsychotic drug
negative and cognitive
symptoms Postsynaptic receptor
To preserve physiologic
function in DA neurons that
regulate movement and Postsynaptic neuron
prolactin secretion
38. Typical Antipsychotic limitation:
Treatment Resistance
• Poor treatment response in 30% of
treated patients
• Incomplete treatment response in
an additional 30% or more
39. The First “Atypical” Antipsychotic:
Clozapine
• FDA approved 1990
• For treatment-resistant schizophrenia
• 30% response rate in severely ill,
treatment-resistant patients (vs. 4%
with chlorpromazine/Thorazine)
• Receptor differences: Less D2 affinity,
more 5-HT
10
40. Clozapine: pros and cons
• Superior efficacy for positive symptoms
• Possible advantages for negative symptoms
• Virtually no EPS or TD
• Advantages in reducing hostility, suicidality
• Associated with agranulocytosis (1-2%)
– WBC count monitoring required
• Seizure risk (3-5%)
• Warning for myocarditis
• Significant weight gain, sedation, orthostasis,
tachycardia, sialorrhea, constipation
• Costly
• Fair acceptability by patients
42. Defining “atypical” antipsychotic
Relative to conventional drugs:
• Lower ratio of D2 and 5-HT2A receptor
antagonism
• Lower propensity to cause EPS
(extrapyramidal side effects)
43. Atypical Antipsychotics:
Efficacy
• Effective for positive symptoms
• (equal or better than typical antipsychotics)
• Clozapine is more effective than
conventional antipsychotics in treatment-
resistant patients
• Atypicals may be better than
conventionals for negative symptoms
44. Atypical Antipsychotics:
Efficacy for Cognitive and Mood
Symptoms
• Atypical antipsychotics may improve
cognitive and mood symptoms
(Typical antipsychotics tend to worsen
cognitive function)
• Dysphoric mood may be more
common with typical antipsychotics
45. Atypical Antipsychotics:
Side Effects
• Atypical antipsychotics tend to have
better subjective tolerability (except
clozapine)
• Atypical antipsychotics much less likely
to cause EPS and TD, but may cause
more:
• Weight gain
• Metabolic problems (lipids, glucose)
• ECG changes
46. Ideal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and
affective symptoms
Earlier and more globally these manifestations
are arrested, the better the long-term prospects.
Overall safety D2
↓↓EPS
↓↓Hyperprolactinemia
Metabolically neutral
5-HT2
47. Current consensus on
antipsychotics
• Atypical antipsychotics (other than clozapine)
are first choice drugs:
-superiority on EPS and TD
-at least equal efficacy on + and – symptoms
-possible advantages on mood and cognition
• BUT:
-long-term consequences of weight gain and
metabolic effects may alter recommendation
-atypicals are very expensive
51. Aspects of tight and loose antipsychotic
binding at Dopamine D2 receptors
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk Low risk
Less lipophilic
54. dopamine neuron
Substantia 5HT2A
nigra receptor
serotonin neuron
Raphe
55. Differences among Antipsychotic
Drugs
• All effective antipsychotic drugs block D2 receptors
• Chlorpromazine and thioridazine
– block α1 adrenoceptors more potently than D2 receptors
– block serotonin 5-HT2 receptors relatively strongly
– affinity for D1 receptors is relatively weak
• Haloperidol
– acts mainly on D2 receptors
– some effect on 5-HT2 and α1 receptors
– negligible effects on D1 receptors
• Pimozide and amisulpride†
– act almost exclusively on D2 receptors
56. Differences among Antipsychotic
Drugs
• Clozapine
– binds more to D4, 5-HT2, α1, and histamine H1
receptors than to either D2 or D1 receptors
• Risperidone
– about equally potent in blocking D2 and 5-HT2
receptors
• Olanzapine
– more potent as an antagonist of 5-HT2 receptors
– lesser potency at D1, D2, and α1 receptors
• Quetiapine
– lower-potency compound with relatively similar
antagonism of 5-HT2, D2, α1, and α2 receptors
57. Differences among Antipsychotic
Drugs
• Clozapine, olanzapine and quetiapine
– potent inhibitors of H1 histamine receptors
– consistent with their sedative properties
• Aripiprazole
– partial agonist effects at D2 and 5-HT1A
receptors
Why do you care? The issue is that everybody wants to get rid of positive symptoms. For a long time, that was what the conventional antipsychotics did, and that was enough. But if positive symptoms go away, we don't cure patients -- they don't go back to work, and they're not in remission -- so that's not enough. You can even get rid of some aggressive symptoms with just D2 blockade. What the addition of serotonin 2A antagonism did was not to interfere with that property.
Which Receptor Properties of Second-Generation Atypical Antipsychotics Are "Class" Actions? Which receptor properties of the so-called "second-generation" drugs (which I just showed) are class actions? The answer is that they are all serotonin 2A and D2 dopamine antagonists. They all substantially block D2 receptors at therapeutic doses. If you don't dose them right, then they don't work. But, if you dose them right, they work right. What's wrong with the brain is that it's out of tune. It is not quite clear whether the neurotransmitters are too high and some pathways are too low -- that's kind of an old fashioned way of looking at it -- but they're basically not correct and need to be tuned. This is why you have to titrate the dose of the drug to the patient in order to get the right amount of action at that particular person's receptor sites. From what we can tell, if you don't block a substantial number of their D2 receptors -- however you do it -- patients don't benefit much. We found that all of these drugs have comparable or even greater functional blockade of the other receptor, called the serotonin 2A receptor, if you do it enough.
These problems are not just with typical drugs.
The atypical antipsychotics started with clozapine, and then went to the 5 first-line drugs -- risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. They all have this property; there is no known antipsychotic that doesn't dance on a dopamine (D)2 receptor. Some of them dance and go away fast, called rapid dissociation or "hit and run," and some of them are partial agonists; but, every effective antipsychotic has some D2 action -- even the old drugs. What's new about the new drugs is this 5-hydroxytryptamine 2A receptor (5HT2A) action. They're all, in some ways, dancing upon the serotonin 2A receptor -- that makes them different as a class.
What's So Great About Serotonin 2A Antagonism? What's so great about it is that -- at least in the pathway that's thought to moderate and mediate the delusions, hallucinations, and thought disorders (the positive symptoms) -- this serotonin 2A property doesn't confound that. Every study seems to suggest that they're just as good for positive symptoms. So there may not be an advantage here. Part of a good pharmacologist's repertoire is to understand that the mesolimbic system is where we think the positive symptoms live. What really made these drugs different was their ability to block a little of the dopamine actions in the nigrostriatal pathway. When you block enough receptors in the striatum, you get parkinsonism; if you just pull back from the edge a couple of percentages, you don't. These new drugs were able to reduce enough D2 binding so that they became quite clearly special -- and were coined, by Dr. Meltzer, "atypical antipsychotics." What does that mean? Some people would say his original definition was that it's a drug that has positive symptom reduction without extrapyramidal symptoms (EPS). Others would say other things, but the issue is that they don't have the EPS for every pound of antipsychotic action. We've learned more; being on the market now for several years, we found that there's a third pathway. In the cortex, this serotonin 2A property increases dopamine release -- yes, I said increases. Now wait, I thought it decreased dopamine in the mesolimbic area. It does, but it actually causes a lot of dopamine release in the cortex. Wouldn't that be self-defeating? The answer is no -- because God didn't put D2 receptors in very big concentrations in the front of the brain. So if the receptor is not there, you can't block it. If you increase dopamine in the cortex, the D2 property is moot because you want to stimulate D1 receptors. What is very interesting about this is that you do not interfere with the dopamine blockade in the mesolimbic area. You interfere just a little bit with it in the striatum, so you don't get EPS. And then you overwhelm the cortex with so much dopamine that it actually stimulates D1 receptors in the brain at the same time. Can you imagine if they had actually tried to do that on purpose? It was an accident, but we're sure glad.
What's So Great About Serotonin 2A Antagonism? What's so great about it is that -- at least in the pathway that's thought to moderate and mediate the delusions, hallucinations, and thought disorders (the positive symptoms) -- this serotonin 2A property doesn't confound that. Every study seems to suggest that they're just as good for positive symptoms. So there may not be an advantage here. Part of a good pharmacologist's repertoire is to understand that the mesolimbic system is where we think the positive symptoms live. What really made these drugs different was their ability to block a little of the dopamine actions in the nigrostriatal pathway. When you block enough receptors in the striatum, you get parkinsonism; if you just pull back from the edge a couple of percentages, you don't. These new drugs were able to reduce enough D2 binding so that they became quite clearly special -- and were coined, by Dr. Meltzer, "atypical antipsychotics." What does that mean? Some people would say his original definition was that it's a drug that has positive symptom reduction without extrapyramidal symptoms (EPS). Others would say other things, but the issue is that they don't have the EPS for every pound of antipsychotic action. We've learned more; being on the market now for several years, we found that there's a third pathway. In the cortex, this serotonin 2A property increases dopamine release -- yes, I said increases. Now wait, I thought it decreased dopamine in the mesolimbic area. It does, but it actually causes a lot of dopamine release in the cortex. Wouldn't that be self-defeating? The answer is no -- because God didn't put D2 receptors in very big concentrations in the front of the brain. So if the receptor is not there, you can't block it. If you increase dopamine in the cortex, the D2 property is moot because you want to stimulate D1 receptors. What is very interesting about this is that you do not interfere with the dopamine blockade in the mesolimbic area. You interfere just a little bit with it in the striatum, so you don't get EPS. And then you overwhelm the cortex with so much dopamine that it actually stimulates D1 receptors in the brain at the same time. Can you imagine if they had actually tried to do that on purpose? It was an accident, but we're sure glad.
What's So Great About Serotonin 2A Antagonism? What's so great about it is that -- at least in the pathway that's thought to moderate and mediate the delusions, hallucinations, and thought disorders (the positive symptoms) -- this serotonin 2A property doesn't confound that. Every study seems to suggest that they're just as good for positive symptoms. So there may not be an advantage here. Part of a good pharmacologist's repertoire is to understand that the mesolimbic system is where we think the positive symptoms live. What really made these drugs different was their ability to block a little of the dopamine actions in the nigrostriatal pathway. When you block enough receptors in the striatum, you get parkinsonism; if you just pull back from the edge a couple of percentages, you don't. These new drugs were able to reduce enough D2 binding so that they became quite clearly special -- and were coined, by Dr. Meltzer, "atypical antipsychotics." What does that mean? Some people would say his original definition was that it's a drug that has positive symptom reduction without extrapyramidal symptoms (EPS). Others would say other things, but the issue is that they don't have the EPS for every pound of antipsychotic action. We've learned more; being on the market now for several years, we found that there's a third pathway. In the cortex, this serotonin 2A property increases dopamine release -- yes, I said increases. Now wait, I thought it decreased dopamine in the mesolimbic area. It does, but it actually causes a lot of dopamine release in the cortex. Wouldn't that be self-defeating? The answer is no -- because God didn't put D2 receptors in very big concentrations in the front of the brain. So if the receptor is not there, you can't block it. If you increase dopamine in the cortex, the D2 property is moot because you want to stimulate D1 receptors. What is very interesting about this is that you do not interfere with the dopamine blockade in the mesolimbic area. You interfere just a little bit with it in the striatum, so you don't get EPS. And then you overwhelm the cortex with so much dopamine that it actually stimulates D1 receptors in the brain at the same time. Can you imagine if they had actually tried to do that on purpose? It was an accident, but we're sure glad.
