PHARMACOLOGY OF DOPAMINE

Maria Qibtia
OVERVIEW
• Introduction
• Synthesis
• Dopamine receptors
• Dopaminergic pathways
• Drug related to dopamine system
• Conclusion
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
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 influx
DOPAMINE RECEPTORS
Subtypes Location Function

D1 Putamen, nucleus Inhibition causes

accumbens i.e extrapyrimidal
nigrostrial pathway disorders
D2 Striatum, substantia Control
nigra , pituitary 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
DRUGS MODIFYING DOPAMINERGIC
TRANSMISSION
Mechanism Drug Effect Use

Synthesis L-DOPA ↑ Synth Parkinsons disease

2 methyl-p- Inhibits tyrosine expts

tyrosine hydroxylase
Carbidopa , Inhibit dopa Parkinsonism
Benserazide decarboxylase
Storage Reserpine, Disrupt storage Tranquilizer
Tetrabenzine
MAO inhibitors Enhance storage

Release Amphetamine, Release Anorectic, CNS

Tyramine, dopamine on stimulant
Mazindole receptors
DRUGS MODIFYING DOPAMINERGIC
TRANSMISSION

Mechanism Drug Effect Use

Inactivation of Amphetamine, CNS stimulant

uptake Cocaine,
Anorectic
Benztropine Parkinson's
Benzhexol disease

Inactivation of Iproniazid, Nonselective

metabolism Tranylcypromine, MAO inhibitors

Selegiline MAO inhibitors Parkinson's

disease
DOPAMINE ANTAGONISTS IN SCHIZOPHRENIA

Antipsychotic Mechanism of effects toxicity

Typical action

Phenothiazines Blockade of Also blocker of Akathisia,Dyston

: D2>>5HT2A alpha,M,H1. ia, parkinson
-chlorpromazine symptom ,tardive
-fluphenazine dyskinesia,
-thioridazine hyperprolactine
Thioxanthenes mia
Thiothixene
flupenthixol
Butyrophenone Blockade of Alpha and Extrapyrimidal
s D2>>5HT2A minimal M dysfunction
Haloperidol blockade
Droperidol
domperidone
Antipsychotic Mechanism of effects toxicity
Atypical action

Aripiprazole Blockade of Some alpha Agranulocytosi

Clozapine 5HT2A>D2 and M s(Clozapine),W
Olanzapine blockade and eight gain, low
Quetiapine variable H1 seizure
Risperidone blockade threshold,catra
Ziprasidone ct,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
subclass effect Pharmacokinetic, toxicity and
interaction
Levodopa -Ameliorates all symptoms Oral ~ 6–8 h
of Parkinson's disease Toxicity: GI upset, arrhythmias,
-significant peripheral dyskinesias, on-off and wearing-off
dopaminergic effects phenomena, behavioral disturbances

Interactions: Use with carbidopa

greatly diminishes required dosage,

levodopa+Car Carbidopa inhibits Use with COMT or MAO-B inhibitors

bidopa peripheral metabolism of prolongs duration of effect.
levodopa
Dopamine Reduces symptoms, Oral ~ 8 h
agonists Toxicity: Nausea and vomiting,
Pramipexole Smooths out fluctuations postural hypotension, dyskinesias
(D3Agonist) in levodopa response
Ropinirole
Bromocriptine
Apomorphine
 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
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 following
effects:
 Hasten esophageal clearance.
 Increase tone of the gastro-esophageal sphincter.

 Accelerate gastric emptying.

 Antiemetic effects by dopamine (D2) blockade.

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
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.
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.
THANK
YOU