Pharmacology of dopamine

PHARMACOLOGY OF DOPAMINE

Dr.Sumit Wankhede

JR3,

sumeetwankhede@gmail.com

8308833593

IGGMC,Nagpur

OVERVIEW

• Introduction• Synthesis • Dopamine receptors• Dopaminergic pathways• Drug related to dopamine system• Recent Researches• Conclusion

2

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

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

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

DOPAMINERGIC PATHWAYS

• Mesolimbic Pathway• Mesocortical Pathway• Nigrostriatal Pathway• Tuberoinfundibular

Pathway• Incertohypothalamic

Pathway• Medullary

Periventricular• Retinal

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

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

15

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)

20

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

28

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

THANK YOU