Moderator

Dopaminergic system & therapeutic applications

Dr Siddhartha DuttaMAMC, New Delhi

Introduction Dopamine receptors Dopaminergic pathways Pathologies associated with dopamine system Drugs modulating dopaminergic system Dopamine and Reward Signaling ,Addiction, ADHD

& Schizophrenia Dopamine and CVS Dopamine and Emesis Summary

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Contents

History Synthesized by George Barger and James Ewens in

1910

Henry Dale characterized the biological properties of DA in the periphery, and described it as a weak, adrenaline-like substance

Was considered as just a precursor to Epinephrine and Norepinephrine

Function as neurotransmitter discovered by Arvid Carlsson in 1958

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Synthesis• DOPA is converted so

rapidly into Dopamine that DOPA levels are negligible in the brain

• Rate of synthesis is regulated by– Catecholamine acting as

inhibitor of TH– Availability of BH4

– Presynaptic DA receptors– Amount of activity in

nigrostriatal pathway 4

Rate Limiting Step

Metabolism• In rats – DOPAC major

metabolite

• In primates and human – HVA major metabolite

• Accumulation of HVA in brain or CSF used as index of function of dopaminergic neurons

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Dopamine Receptors Metabotropic G-protein coupled receptors

D1 – like family:◦ Includes subtypes D1 and D5

◦ Activation is coupled to Gαs ; activates adenylyl cylcase which leads to increase in concentration of cAMP

D2 – like family: ◦ Includes D2, D3 and D4

◦ Activation is coupled to Gαi ; inhibits adenylyl cyclase leading to decrease in concentration of cAMP

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Dopamine Receptors

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CNS

CVS

GIT

Modulation of dopaminergic system

Dopaminergic pathways

Mesolimbic Pathway

Mesocortical Pathway

Nigrostriatal Pathway

Tuberoinfundibular Pathway

Dopaminergic pathways

Significance of Dopaminergic Pathways Mesolimbic Pathway

◦ Associated with pleasure, reward and goal directed behavior

Mesocortical Pathway◦ Associated with motivational and emotional

responses

Nigrostriatal Pathway◦ Involved in coordination of movement (part of basal

ganglia motor loop)

Tuberoinfundibular Pathway◦ Regulates secretion of prolactin by pituitary gland

and involved in maternal behavior 20

Pathologies associated with dopamine system

INCREASED DOPAMINE DECREASED DOPAMINE

SCHIZOPHRENIA PARKINSON’S DISEASE ADHD IMPULSE CONTROL

DISORDER DRUG ADDICTION HYPERPROLACTINEMIA

Parkinson’s Disease

Parkinson’s disease is a clinical syndrome consisting of four cardinal features:

Bradykinesia

Muscular rigidity

Resting tremor

Postural instability

Pathophysiology

Dopamine precursor : Levodopa

Peripheral decarboxylase inhibitors: Carbidopa, Benserazide

Dopaminergic agonists: Bromocriptine, Ropinirole, Pramipexole, Apomorphine

MAO-B inhibitor: Selegiline, Rasagiline

COMT inhibitors: Entacapone, Tolcapone Dopamine facilitator: Amantadine

Pharmacotherapy

Mechanism of Action

Drug Pharmacokinetic and interaction

effect Adverse effects

Levodopa Oral

T ½ - 1-2 h

Dose: 250- 1200 mg

>95% is decarboxylated in the peripheral tissues (mainly gut and liver)

Use with COMT or MAO-B inhibitors prolongs duration of effect

Ameliorates all symptoms of PD

Hypokinesia and rigidity resolve first, later tremor as well

significant peripheral dopaminergic effects

Postural hypotension

Nausea & vomiting

inhibit prolactin release

Arrhythmias

Dyskinesias

Behavioral effects

Motor fluctuation wearing-off phenomena/end of dose

On off phenomena

Drug Pharmacokinetic and interaction

effect Adverse effects

Levodopa • Oral• T ½ - 1-2 h

• Dose: 250- 1200 mg • >95% is

decarboxylated in the peripheral tissues (mainly gut and liver)

• Use with COMT or MAO-B inhibitors prolongs duration of effect

• Ameliorates all symptoms of PD

• Hypokinesia and rigidity resolve first, later tremor as well

• Nausea & vomiting

• inhibit prolactin release

• significant peripheral dopaminergic effects

Postural hypotension

Nausea & vomiting Arrhythmias

Dyskinesias

Behavioral effcts

on-off and wearing-off phenomena

Levodopa +Carbidopa

200 mg/ 100mg+ 50mg / 25 mg

2-3 times a day

• T ½ of levodopa is prolonged & dosage is reduced to ¼ th

• Systemic

complications of DA are reduced

• 'On-off' effect is minimized as cerebral DA levels are more sustained.

• Involuntary movements

• Behavioral abnormalities

• Excess day time sleepiness

• Postural hypotension

Dopamine agonists

Pharmacokinetic, Effect/ distinguishing features

toxicity and interaction

Bromocriptine Oral T ½ -6-10 hrs

Dose: 1.25-5 mg O.D

If used alone, doses needed are high

used only in late casesReduces symptoms

Smooths out fluctuations in levodopa response

Nausea and vomiting

postural hypotension,

dyskinesias

Pramipexole Oral

T ½- 8 h

Starting dose-0.125 mg TDS

1-1.5 mg TDS

Reduces symptoms,

Smooths out fluctuations in levodopa response

dose titration for maximum improvement can be achieved in 1-2 weeks

Fewer GI effects

Nausea and vomiting

Postural hypotension

Day time sleepiness

HallucinationsRopinirole Starting dose-0.25mg

TDS 4-8 mg TDS

Slower rates of neuronal degeneration ??

FDA approved for Restless Leg Syndrome

Sudden attack of irresistible sleepiness

Drug Pharmacokinetics

Features and effect Adverse effects

Apomorphine S.C

2 mg test dose ↓6 mg

Inj 3 times daily

High affinity - D4Mod affinity - D2,3,5low affinity - D1

FDA approved as a "rescue therapy"

Lessens motor fluctuations

Reduced frequency of on-off effect

Restless leg syndrome

Nausea and vomiting

postural hypotension

QT prolongation

Injection-site reactions,

Hallucinations

Dyskinesia

Abnormal behavior

Blocking metabolism

MAO- B inhibitors

Pk Features Adverse effects

Selegiline

Oral

5- 10 mg/ day

BD dosing

Oral disintegrating tab

Transdermal patch

selective and irreversible MAO-B inhibitor

Increases dopamine stores in neurons

Adjuvant to levodopa

20-30% reduction in levodopa dose

May accentuate the adverse motor and cognitive effects of levodopa

Metabolites of include amphetamine and methamphetamine, which may cause anxiety, insomnia, and other adverse symptoms

Do not exhibit cheese reaction

Postural hypotension

Dyskinesias,

Mental confusion

Hallucination

C/I in patients with siezures

Interactions: rarely serotonin syndrome with meperidine, also with SSRIs, TCA

MAO- B inhibitors

Pk Features Adverse effects

Selegiline Oral

5- 10 mg/ day

Oral disintegrating tab

Transdermal patch

selective and irreversible MAO-B inhibitor

Increases dopamine stores in neurons

Adjuvant to levodopa

20-30% reduction in levodopa dose

May accentuate the adverse motor and cognitive effects of levodopa

Metabolites of include amphetamine and methamphetamine, which may cause anxiety, insomnia, and agitation

Do not exhibit cheese reaction

Postural hypotensionDyskinesias,Mental confusion or hallucinationC/I in patients with siezures

Interactions: serotonin syndrome with meperidine, also with SSRIs, TCA

Rasagiline 5x potent

0.5-1.0 mg tab

OD dosing

No undesirable amphetamine metabolites

Effective in early PD??

Adjunctive therapy significantly reduced levodopa-related "wearing off" symptoms

Neuroprotective (Parkinson Study Group, 1993; Yacoubian and Standaert, 2008, Olanow, 2008, ).

Stupor, rigidity, agitation, and hyperthermia when administered with Meperidine

COMT inhibitors 

Pk Features Adverse effects

Entacapone

Oral

600-2000 mg

BD or TDS

Adjuvants to levodopa-carbidopa

Advanced cases

Reduces metabolism of levodopa and prolongs its action

Increased levodopa conc

Nausea

Dyskinesias

confusion 

Postural hypotension

Tolcapone Oral

100-300 mg

BD or TDS

Longer acting

Enters CNS

Hepatotoxic??

Drugs Pk Features Adverse effects

Glutamate (NMDA receptor) antagonist

Amantadine

Oral

T ½ 8 to 12 hrs

100 mg BD

Promotes presynaptic synthesis & release of DA in brain

Suppresses motor fluctuations & abnormal movements

Smoothen wearing off

Anticholinergic property

Insomnia RestlessnessConfusionNightmaresHallucination Livedo reticularisAnkle edema

Dopamine and Reward Signaling

Addiction and drug abuse

Occasional substance use is an impulse choice driven by positive reinforcement of the drug’s expected effect

This teaches the brain to anticipate reward on subsequent exposure to the drug

When the substance is taken, pleasure will be experienced again, usually followed by regret

Impulsive cycle

With repeated exposure to the drug neurobiological changes occur in the brain

leads to craving, reduced reward on drug exposure withdrawal during abstinence (negative reinforcement)

This leads to craving which is released by drug ingestion

Compulsive cycle

Nucleus Accumbens Occurs due to increased release of dopamine

caused by the psychotropic substances like morphine heroin Cannabis cocaine nicotine

Substance Abuse

Attention deficit hyperactivity disorder Decrease In Dopamine Level in Anterior frontal cortex

◦ An area associated with cognitive function such as Attention Concentration

Defects in “dopamine transporters” in brain

Dopamine transporter density (DTD)

The transporters take up too much dopamine before it can be passed from one brain cell to another

Decreased dopamine activity

Dopamine & ADHD

Methylphenidate and Amphetamine

Increase both dopamine and norepinephrine levels in brain

Methylphenidate-5 mg at morning & lunch gradually increased to 60 mg

10-30 mg/ day amphetamine

Adverse effects Restlessness, dizziness, tremor, hyperactive reflexes,

talkativeness, irritability, insomnia & euphoria. Confusion, aggressiveness & delirium

Pharmacotherapy

Dopaminergic Tubero-infundibular tract & hypophyseal portal system

Hyperprolactinemia

Bromocriptine Start at a low dose (1.25 mg) at bedtime After 1 week,

a morning dose of 1.25 mg can be added. If clinical symptoms persist or prolactin levels remain

elevated, the dose can be increased gradually, every 3-7 days

5 mg BD or TDS as tolerated

Cabergoline Ergot derivative with a longer t1/2 (65 hours) Higher affinity & greater selectivity for the D2

receptor ( 4x potent) than bromocriptine Induces remission 0.25 mg twice/week or 0.5 mg once/week can be ↑ to

2mg twice or thrice /week

Schizophrenia Defective dopamine neurotransmission – relative

excess of central dopaminergic activity

An increase in DA function in the mesolimbic system (postive symptom)

Decreased function in the mesocortical DA system (negative symptoms)

Behavior similar to the behavioral effects of psychostimulants

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Came to existence from the fortuitous discovery of chlorpromazine's therapeutic efficacy in schizophrenia

Carlsson – Postsynaptic D2 receptor antagonism was the common

mechanism that explained antipsychotic properties

Reserpine, exhibited antipsychotic properties by decreasing dopaminergic neurotransmission

High risk for drug-induced psychosis with drugs that directly increase synaptic dopamine availability, including cocaine, amphetamines & L-dopa

Dopamine hypothesis..

Synaptic DA availability Val{108/158} Met polymorphism of COMT DA neurotransmission (dysbindin)

Genetic basis

Dopamine antagonists in schizophreniaAntipsychoticTypical

Mechanism of action

Toxicity

Phenothiazines:

• Chlorpromazine• Fluphenazine• Thioridazine• Thioxanthenes• Thiothixene• flupenthixol

Blockade of D2>>5HT2A

Also blocker of alpha 1, M, H1

Akathisia,Dystonia,Parkinson symptom Tardive dyskinesia, Hyperprolactinemia

Butyrophenones

• Haloperidol• Droperidol• Domperidone

Blockade of D2>>5HT2A

Alpha 1and minimal M 1blockade

Extrapyrimidal dysfunction

AntipsychoticAtypical

Mechanism of action toxicity

• Aripiprazole• Clozapine• Olanzapine• Quetiapine• Risperidone• Ziprasidone• Paliperidone • Iloperidone

Blockade of 5HT2A>D2

Alpha1&M 1blockade variable H1 blockade

Agranulocytosis(Clozapine)Weight gainlower seizure thresholdCatractQT prolongation

Dopamine and CVS

D1 and D2 β 1 & α1 agonist Effect on CVS is dose dependent

Dopamine and CVS

Low dose1-2 mcg/kg/min

Moderate dose 3-10mcg/kg/min

High dose >10 mcg/kg/min

D 1renal and mesen teric blood vessels dilates

β 1↑ H.R↑ contractility↑ AV conduction

α₁ action predominatesvasoconstriction

↑ G.f.r.↑ Renal blood flow Natriuresis

↑ C.O & SBP

TPR unaltered

TPR ↑

C.O & SBP with little effect on DBP No effect on nonvascular α₁ receptors Does not penetrate blood-brain barrier-no CNS effects

Management of low cardiac output states associated with compromised renal function

IV infusion (0.2-1 mg/min) which is regulated by monitoring BP and rate of urine formation

Dopamine -only IV, preferably into a large vein calibrated infusion pump

Dosage Initially at a rate of 2-5 mcg/kg per min; this rate may be

increased gradually up to 20-50 mcg/kg per min or more

Monitoring of arterial and venous pressures and the ECG

Adverse effects & precautions

Nausea, tachycardia, anginal pain, arrhythmias, HTN headache Extravasation of DA during infusion may cause ischemic

necrosis and sloughing

Low output states & oliguria

Agonist for peripheral D1 receptors and antagonist to α2 receptors

No significant affinity for D2, α 1 or β receptors

Rapidly acting(4 mins) and short duration of action (< 10 minutes) vasodilator used for control of

severe hypertension

Dilates Coronary arteries, renal afferent and efferent arterioles and mesenteric arteries

Dosage Calibrated infusion pump @ 01-1.6 g/kg per min

Adverse effects are related to the vasodilation and include headache, flushing, dizziness, and tachycardia or bradycardia

Fenoldopam

Synthetic analog related to DA

D1 and D2 receptors as well as at β2 receptors

Patients with severe congestive heart failure, sepsis, and shock

Patients with low cardiac output, significantly increases stroke volume with a decrease in SVR

Tachycardia and hypotension can occur, usually only at high infusion rates

Dopexamine

Dopamine & emesis

Blocks D2-receptors, agonist at 5HT4 and in high doses blocks 5-HT3

Antiemetic action

Accelerate gastric emptying (prokinetic)

Raises LES pressure

Increases intestinal peristalsis

Metoclopramide

PK Orally it acts in ½ to 1 hr 10 min after I.M. and 2 min after I.V. inj Action lasts for 4-6 hours

Interactions Hastens the absorption of many drugs, e.g. aspirin,

diazepam(facilitating gastric emptying) It reduces absorption of digoxin Blocks D2 in basal ganglia, abolishes the therapeutic effect of

levodopa

Adverse effects Sedation, dizziness, loose stools, muscle dystonias

Long-term use can cause parkinsonism, galactor rhoea and gynaecomastia.

Prokinetic action is not blocked by atropine and is based only on D2 blockade in upper g.i.t.

Crosses BBB poorly

levodopa or bromocriptine, it counteracts their dose limiting emetic action without affecting the therapeutic effect in parkinsonism

Oral 10-40 mg TDS, BA ~15% due to FPM

EPS are rare, but hyperpro lactinaemia can occur

Cardiac arrhythmias on rapid i.v. injection.

Domperidone

Metoclopramide or Domperidone ?

Which is a better antiemetic??

Phenothiazines & Butyrophenones Phenothiazines

Prochlorperazine Promethazine

Phenothiazines are antipsychotics with potent antiemetic property due to D2 antagonism.

Butyrophenone Droperidol

Droperidol used for postop. nausea & vomiting, but cause QT prolongation.

Thank you