PHARMACOLOGY OF DOPAMINE
Dr.Sumit Wankhede
JR3,
8308833593
IGGMC,Nagpur
OVERVIEW
• Introduction• Synthesis • Dopamine receptors• Dopaminergic pathways• Drug related to dopamine system• Recent Researches• Conclusion
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INTRODUCTION
Dopamine belongs to the family of catecholamines
Hormones, Epinephrine and Norepinephrine (other catecholamines) are derived from Dopamine
Significant role in learning, goal-directed behavior, regulation of hormones, motor control
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DA SYNTHESIS AND METABOLISM L phenylalanine (amino acid from diet)
phenyalanine hydroxylase L- Tyrosine Tyrosine hydroxylase RLS
L Dopa Dopa decarboxylase Dopamine (DA)
Monoamine oxidase (MAO) Catechol-O-methyl transferase (COMT)
DOPAC + HVA
After synthesis, dopamine is packaged into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored there until its release into the synapse during neurotransmission.
DOPAMINE RECEPTORS
• Metabotropic G-protein coupled receptors• D1 – like family:
– Includes subtypes D1 and D5
– Activation is coupled to Gs ; activates adenylyl cylcase which leads to increase in concentration of cAMP
• D2 – like family: – Includes D2, D3 and D4
– Activation is coupled to Gi ; inhibits adenylyl cyclase leading to decrease in concentration of Camp
– Also open K channels & closes Ca influx7
DOPAMINE RECEPTORS
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Subtypes Location Function
D1 Putamen, nucleus accumbens i.e nigrostrial pathway
Inhibition causes extrapyrimidal disorders
D2 Striatum, substantia nigra , pituitary
Control behaviour,voluntary, prolactin release
D3 Midbrain, mucleus accumbens & hypothalamus
D4 Frontal cortex, medulla and midbrain i.e mesocortical pathway
D5 Hypothalamus , hippocampus
DOPAMINERGIC PATHWAYS
• Mesolimbic Pathway• Mesocortical Pathway• Nigrostriatal Pathway• Tuberoinfundibular
Pathway• Incertohypothalamic
Pathway• Medullary
Periventricular• Retinal
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SIGNIFICANCE OF DOPAMINERGIC PATHWAYS
• Mesolimbic Pathway– Associated with pleasure, reward and goal
directed behaviour• Mesocortical Pathway
– Associated with motivational and emotional responses
• Nigrostriatal Pathway– Involved in coordination of movement (part of
basal ganglia motor loop/EPS)• Tuberoinfundibular Pathway
– Regulates secretion of prolactin by pituitary gland and involved in maternal behavior
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DRUGS MODIFYING DOPAMINERGIC TRANSMISSION
Mechanism Drug Effect Use
Synthesis L-DOPA ↑ Synth Parkinsons disease
2 methyl-p- tyrosine
Inhibits tyrosine hydroxylase
expts
Carbidopa , Benserazide
Inhibit dopa decarboxylase
Parkinsonism
Storage Reserpine, Tetrabenzine
Disrupt storage Tranquilizer
MAO inhibitors Enhance storage
Release Amphetamine, Tyramine, Mazindole
Release dopamine on receptors
Anorectic, CNS stimulant
DRUGS MODIFYING DOPAMINERGIC TRANSMISSIONMechanism Drug Effect Use
Inactivation of uptake
Amphetamine, Cocaine,
CNS stimulant
Anorectic
BenztropineBenzhexol
Parkinson's disease
Inactivation of metabolism
Iproniazid, Tranylcypromine,
Nonselective MAO inhibitors
Selegiline MAO inhibitors Parkinson's disease
SCHIZOPHRENIA
Defective dopamine neurotransmission – relative excess of central dopaminergic activity
An increase in DA function in the mesolimbic system and a decreased function in the mesocortical DA systems(D1 predominates)
Behavior similar to the behavioral effects of psychostimulants
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DOPAMINE HYPOTHESISOF SCHIZOPHRENIA
DOPAMINE ANTAGONISTS IN SCHIZOPHRENIA
AntipsychoticTypical
Mechanism of action
effects toxicity
Phenothiazines:-chlorpromazine-fluphenazine-thioridazineThioxanthenesThiothixeneflupenthixol
Blockade of D2>>5HT2A
Also blocker of alpha,M,H1.
Akathisia,Dystonia, parkinson symptom ,tardive dyskinesia, hyperprolactinemia
ButyrophenonesHaloperidolDroperidoldomperidone
Blockade of D2>>5HT2A
Alpha and minimal M blockade
Extrapyrimidal dysfunction
AntipsychoticAtypical
Mechanism of action
effects toxicity
AripiprazoleClozapineOlanzapineQuetiapineRisperidoneZiprasidone
Blockade of 5HT2A>D2
Some alpha and M blockade and variable H1 blockade
Agranulocytosis(Clozapine),Weight gain, low seizure threshold,catract,QT prolongation
PARKINSON’S DISEASE
Parkinson’s sufferers have low levels of dopamine
L-dopa raises DA activity People with Parkinson's develop
schizophrenic symptoms if they take too much L-dopa
PARKINSON’S DISEASE
Substantial loss of Dopamine in the striatum (70 – 80%)
Loss of dopamine neurons in other systems also (mesolimbic, mesocortical and hypothalamic systems)
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Treatment strategy includes – increasing dopamine levels nerve grafting with dopamine containing
cells and deep brain stimulation
subclass effect Pharmacokinetic, toxicity and interaction
Levodopa
levodopa+Carbidopa
-Ameliorates all symptoms of Parkinson's disease -significant peripheral dopaminergic effects
Carbidopa inhibits peripheral metabolism of levodopa
Oral ~ 6–8 h Toxicity: GI upset, arrhythmias, dyskinesias, on-off and wearing-off phenomena, behavioral disturbances
Interactions: Use with carbidopa greatly diminishes required dosage,
Use with COMT or MAO-B inhibitors prolongs duration of effect.
Dopamine agonistsPramipexole (D3Agonist)
Reduces symptoms,
Smooths out fluctuations in levodopa response
Oral ~ 8 hToxicity: Nausea and vomiting, postural hypotension, dyskinesias
RopiniroleBromocriptineApomorphine
subclass effect Pharmacokinetic, toxicity and interaction
MAO inhibitorsSelegiline Rasagiline
Increases dopamine stores in neurons;
Oral Toxicity & interactions: may cause serotonin syndrome with meperidine also with SSRIs, tricyclic antidepressants
COMT inhibitors Entacapone
Tolcapone
Reduces metabolism of levodopa and prolongs its action
Enters CNS
Oral Toxicity: Increased levodopa toxicity nausea, dyskinesias, confusion
Other motor disorders: Huntington’s disease Tourrette’s syndrome
D2 Blockers –Chlorpromazine , Haloperidol
MOTOR CONTROL OF DOPAMINE
ATTENTION DEFICIT HYPERACTIVITY DISORDER
Altered dopamine neurotransmission is implicated in attention deficit hyperactivity disorder (ADHD)
There are some genetic links between dopamine receptors, the dopamine transporter and ADHD.
Some of the most effective therapeutic agents for ADHD are psychostimulants-> methylphenidate and amphetamine : increase both dopamine and norepinephrine levels in brain.
DOPAMINE AND ADDICTION
Almost all dependence producing drugs mesolimbic dopaminergic projection to ventral striatum --- mechanisms for addiction
Psychostimulants such as Cocaine and Amphetamine -- alter dopamine activity in brain
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ROLE OF DOPAMINE IN VOMITING PHENOTHIAZINES• Phenothiazines as prochorperazine ,promethazine
are antipsychotic agents
• Use: • Chemotherapy-induced vomiting• Radiotherapy-induced vomiting• postoperative nausea and vomiting
• Mechanism of the antiemetic action: inhibition of central dopamine D2 on CTZ, muscarinic and H1 histamine receptors receptors
BUTYROPHENONES
• Butyrophenones as droperidole are antipsychotic agents
• Mechanism of the antiemetic action: inhibition of central dopamine receptors
• Use: • Chemotherapy-induced vomiting• Radiotherapy-induced vomiting• postoperative nausea and vomiting• Adverse effects: QT prolongation
PROKINETIC DRUGS
(Metoclopramide & domperidone)The Prokinetic drugs produce the followingeffects: Hasten esophageal clearance. Increase tone of the gastro-esophageal
sphincter. Accelerate gastric emptying. Antiemetic effects by dopamine (D2)
blockade.
Antagonise D2 receptors in CTZ.
Drugs available
Metoclopramide 2.5 mg b.d
Domperidone 10 mg b.d
Domperidone – oral ; Metoclopramide – oral & i.v
Metoclopramide crosses BBB but domperidone cannot.
ROLE OF DOPAMINE O PROLACTIN SECRETION
Inhibits secretion of prolactin by acting on D2 receptors.
Treatment of hyperprolactinemia Ergot derivatives : bromocriptine,
cabergoline, pergolide. Non ergot : Quinagolide
Cabergoline – 0.25(max 1) mg orally twice a week
Quinagolide – 0.2 -0.6 mg orally per day longer t1/2 , better toleratted than ergot derivative Bromocriptine 2.5 mg OD/BD upto 15 days.
ROLE OF DOPAMINE IN RENAL SYSTEM
At low dose (0.5 to 3 micg /kg /min ):- Selectively activates dopamine specific
receptors in the renal and splanchnic circulation.
Increase blood flow in these region. Increase GFR. Increase in urinary Na excretion
HEART AND VASCULATURE
At low concentrations, circulating DA primarily stimulates vascular D1 receptors, causing vasodilation and reducing cardiac afterload.
DA is able to activate adrenergic receptors to further increase cardiac contractility.
The net result is a decrease in blood pressure and an increase in cardiac contractility.
RECENT RESEARCHES
Anti-insulin Analgesic Role in apoptosis Memory Immune
CONCLUSION
The scene is now set for the development of drugs selective for particular receptor subtypes which can be used to elucidate receptor subtype function and treat disorders of dopamine function
REFERENCES
Goodman and Gilman’s The Pharmacological Basis of Therapeutics 12th edi; chap 15,16,22: 932-964
Bertram Katzung ; Basic and clinical pharmacology ; Drug of abuse ;553-568 ;12th edition 2012.
HL Sharma and KK;Antipsychotics ;2nd edition;chap 33; 532-542.
Rang H.P. and Dale M.M;Antipsychotics;7th edition; 39,45,49; 557
Blanca Rubí and Pierre Maechler; Minireview: New Roles for Peripheral Dopamine on Metabolic Control and Tumor Growth; Endocrinology, December 2010, 151(12):5570–5581
http://en.wikipedia.org/wiki/Dopamine
Kaplan & Sadock's Comprehensive Textbook of Psychiatry
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