Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Pharmacology of dopamine

12,264 views

Published on

Pharmacology of dopamine

Published in: Education, Health & Medicine
  • Be the first to comment

Pharmacology of dopamine

  1. 1. PHARMACOLOGY OF DOPAMINE Dr.Sumit Wankhede JR3, sumeetwankhede@gmail.com 8308833593 IGGMC,Nagpur
  2. 2. OVERVIEW • Introduction • Synthesis • Dopamine receptors • Dopaminergic pathways • Drug related to dopamine system • Recent Researches • Conclusion 2
  3. 3. 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 3
  4. 4. 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
  5. 5. 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.
  6. 6. 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 influx 7
  7. 7. DOPAMINE RECEPTORS 8
  8. 8. 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
  9. 9. DOPAMINERGIC PATHWAYS • Mesolimbic Pathway • Mesocortical Pathway • Nigrostriatal Pathway • Tuberoinfundibular Pathway • Incertohypothalamic Pathway • Medullary Periventricular • Retinal 10
  10. 10. 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 12
  11. 11. 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
  12. 12. DRUGS MODIFYING DOPAMINERGIC TRANSMISSION Mechanism Drug Effect Use Inactivation of uptake Amphetamine, Cocaine, CNS stimulant Anorectic Benztropine Benzhexol Parkinson's disease Inactivation of metabolism Iproniazid, Tranylcypromine, Nonselective MAO inhibitors Selegiline MAO inhibitors Parkinson's disease
  13. 13. 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 15
  14. 14. DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA
  15. 15. DOPAMINE ANTAGONISTS IN SCHIZOPHRENIA Antipsychotic Typical Mechanism of action effects toxicity Phenothiazines : -chlorpromazine -fluphenazine -thioridazine Thioxanthenes Thiothixene flupenthixol Blockade of D2>>5HT2A Also blocker of alpha,M,H1. Akathisia,Dyston ia, parkinson symptom ,tardive dyskinesia, hyperprolactine mia Butyrophenone s Haloperidol Droperidol domperidone Blockade of D2>>5HT2A Alpha and minimal M blockade Extrapyrimidal dysfunction
  16. 16. Antipsychotic Atypical Mechanism of action effects toxicity Aripiprazole Clozapine Olanzapine Quetiapine Risperidone Ziprasidone Blockade of 5HT2A>D2 Some alpha and M blockade and variable H1 blockade Agranulocytosi s(Clozapine),W eight gain, low seizure threshold,catra ct,QT prolongation
  17. 17. 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
  18. 18. 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) 20
  19. 19.  Treatment strategy includes –  increasing dopamine levels  nerve grafting with dopamine containing cells and  deep brain stimulation
  20. 20. subclass effect Pharmacokinetic, toxicity and interaction Levodopa levodopa+Car bidopa -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 agonists Pramipexole (D3Agonist) Reduces symptoms, Smooths out fluctuations in levodopa response Oral ~ 8 h Toxicity: Nausea and vomiting, postural hypotension, dyskinesias Ropinirole Bromocriptine Apomorphine
  21. 21. subclass effect Pharmacokinetic, toxicity and interaction MAO inhibitors Selegiline 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
  22. 22.  Other motor disorders:  Huntington’s disease  Tourrette’s syndrome  D2 Blockers –Chlorpromazine , Haloperidol
  23. 23. MOTOR CONTROL OF DOPAMINE
  24. 24. 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.
  25. 25. 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 28
  26. 26. 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
  27. 27. 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
  28. 28. PROKINETIC DRUGS (Metoclopramide & domperidone) The Prokinetic drugs produce the following effects:  Hasten esophageal clearance.  Increase tone of the gastro-esophageal sphincter.  Accelerate gastric emptying.  Antiemetic effects by dopamine (D2) blockade.
  29. 29.  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.
  30. 30. 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
  31. 31.  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.
  32. 32. 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
  33. 33. 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.
  34. 34. RECENT RESEARCHES  Anti-insulin  Analgesic  Role in apoptosis  Memory  Immune
  35. 35. 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
  36. 36. 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.
  37. 37.  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
  38. 38. THANK YOU

×