Pharmacology of dopamine

Pharmacology of dopamine

1. Pharmacology of DOPAMINE Dr.Sumit Wankhede JR3, [email protected] 8308833593 IGGMC,Nagpur

2. Overview Introduction Synthesis Dopamine receptors Dopaminergic pathways Drug related to dopamine system Recent Researches Conclusion 2

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. 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. 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. Dopamine Receptors Metabotropic G-protein coupled receptors D 1 – like family: Includes subtypes D 1 and D 5 Activation is coupled to G s ; activates adenylyl cylcase which leads to increase in concentration of cAMP D 2 – like family: Includes D 2 , D 3 and D 4 Activation is coupled to G i ; inhibits adenylyl cyclase leading to decrease in concentration of Camp Also open K channels & closes Ca influx 7

7. Dopamine Receptors 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. Dopaminergic Pathways Mesolimbic Pathway Mesocortical Pathway Nigrostriatal Pathway Tuberoinfundibular Pathway Incertohypothalamic Pathway Medullary Periventricular Retinal 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. 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. 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. 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. Dopamine Hypothesis of Schizophrenia

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,Dystonia , parkinson symptom ,tardive dyskinesia, hyperprolactinemia Butyrophenones Haloperidol Droperidol domperidone Blockade of D2>>5HT2A Alpha and minimal M blockade Extrapyrimidal dysfunction

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 Agranulocytosis (Clozapine),Weight gain, low seizure threshold,catract,QT prolongation

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. 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. Treatment strategy includes – increasing dopamine levels nerve grafting with dopamine containing cells and deep brain stimulation

20. 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 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. 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. Other motor disorders: Huntington’s disease Tourrette’s syndrome D2 Blockers –Chlorpromazine , Haloperidol

23. Motor control of dopamine

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. 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. 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. 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. 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. Antagonise D 2 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. 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 : Q uinagolide

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. 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. I ncrease GFR. Increase in urinary Na excretion

33. Heart and Vasculature At low concentrations, circulating DA primarily stimulates vascular D 1 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. Recent researches Anti-insulin Analgesic Role in apoptosis Memory Immune

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. references Goodman and Gilman’s The Pharmacological Basis of Therapeutics 12 th edi ; chap 15,16,22: 932-964 Bertram Katzung ; Basic and clinical pharmacology ; Drug of abuse ;553-568 ;12 th edition 2012 . HL Sharma and KK;Antipsychotics ;2 nd edition;chap 33; 532-542.

37. Rang H.P. and Dale M.M ;Antipsychotics;7 th 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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