DOPAMINE

Dr. Fardan Qadeer

Overview:• Introduction• Synthesis and Metabolism• Receptors• Physiologic roles•Pharmacology of Dopamine• Role in Parkinsonism• Role in Disorders of thought• Other Pharmacological roles

INTRODUCTION•Dopamine (DA) is a catecholamine neurotransmitter that is the therapeutic target for a number of important central nervous system (CNS) disorders.

•DA is also a precursor for the other catecholamine neurotransmitters norepinephrine and epinephrine.

•Dopamine belongs to the catecholamine family of neurotransmitters.

SYNTHESIS L phenylalanine (amino acid from diet)

Phenyalanine hydroxylase L- Tyrosine

L Dopa Dopa decarboxylase

Dopamine (DA)

Tyrosine crosses readily into the brain through uptake

Tyrosine Hydroxylase

It is abundant in the brain as well as in the periphery

In Dopaminergic cell the end point of synthesis is Dopamine but at other sites of NE transmission it is converted to NE by dopamine ß hydroxylase

STORAGE & RELEASE

DAT

METABOLISM

MAO are of two types:

MAO-A: Periphery and CNS

MAO-B: CNS

RECEPTORS:• They have been organized into two families—the D1-like and D2-like receptors—based upon their effector-coupling profile

PHYSIOLOGICAL ROLES:SITE ROLEHeart and CV System DA is able to activate ß adrenergic receptors to

further increase cardiac contractilityKidney Renal DA primarily serves to increase

natriuresis, though it can also increase renal blood flow and glomerular filtration

Pituitary Gland DA is the primary regulator of prolactin secretion from the pituitary gland.

Catecholamine Release

The D2 receptor provides tonic inhibition of epinephrine release from chromaffin cells of the adrenal medulla, and of norepinephrine release from sympathetic nerve terminals. In contrast, the D1 receptor responds to high-frequency DA stimulation to promote the release of catecholamines from the adrenal medulla.

GI Tract Abundace of Dopamine receptor initate Emesis CNS

Receptor Distribution

9

CNS regulation• It is by 4 major pathways

The physiological processes under dopaminergic control include reward, emotion, cognition, memory, and motor activity

Pathways Activity DysfunctionThe mesolimbic pathway

Reward and learned behaviors

schizophrenia, and psychoses (including bipolar depression) and learning deficits

Mesocortical pathway

Motivation, reward, emotion, and impulse control

Psychoses, including schizophrenia, and in attention-deficit hyperactivity disorder

Nigrostriatal pathway

regulator of movement

Parkinson disease

Tuberoinfundibular

regulates prolactin secretion.

Hyperprolactinemia

Control of Movement• The largest DA tract in the brain which contains about 80% of the brain’s DA in the nigrostriatal system

•Assisting in learning coordinated movements

Parkinson’s Disease• In Parkinson’s disease, there is a selective loss of dopaminergic neurons in the substantia nigra

• The extent of loss is profound, with at least 70% of the neurons destroyed at the time symptoms first appear

• Etiology:• GENETIC

ENVIRONMENTAL

Treatment of Parkinson’s Disease•Dopamine Precursors:• Levodopa

•Dopamine Agonist• Ropinirole• Pramipexole• Apomorphine

•MAO-B inhibitors• Selegiline• Rasagiline

• COMT inhibitors• Tolcapone • Entacapone

•Non dopaminergic drugs

Levodopa:• Levodopa, the metabolic precursor of Dopamine, is the single most effective agent in the treatment of PD

• Levodopa is itself largely inert; both its therapeutic and adverse effects result from the decarboxylation of levodopa to DA.

• Peak plasma conc. Is between 0.5 and 2 hours after an oral dose. The t1/2 in plasma is short (1-3 hours).

• In clinical practice, levodopa is almost always administered in combination with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase, such as carbidopa or benserazide

Adverse Effects:•Nausea and orthostatic hypotension•Hallucinations and confusion, especially in elderly patients or in patients with pre existing cognitive dysfunction•Motor complications of levodopa:• The patient's motor state may fluctuate dramatically with each dose of levodopa. •Development of the "wearing off" phenomenon: each dose of levodopa effectively improves mobility for a period of time,• In the later stages of PD, patients may fluctuate rapidly between being "off," having no beneficial effects from their medications, and being "on" but with disabling dyskinesias, a situation called the on/off phenomenon

Dopamine-Receptor Agonists• The DA receptor agonists in clinical use have durations of action substantially longer than that of levodopa; they are often used in the management of dose-related fluctuations in motor state.•Modify the course of PD by reducing endogenous release of DA , thereby reducing free radical formation• S/E:• Nausea and orthostatic hypotension• Hallucinations• The somnolence in some cases may be quite severe, and several instances of sudden attacks of irresistible sleepiness.

Apomorphine• Apomorphine is a dopaminergic agonist that can be administered by subcutaneous injection.• It has high affinity for D4 receptors; moderate affinity for D2, D3, D5, and adrenergic receptors; and low affinity for D1 receptors. • FDA-approved as a "rescue therapy" for the acute intermittent treatment of "off" episodes in patients with a fluctuating response to dopaminergic therapy

Enzyme Inhibitors:• Two groups of drugs• COMT inhibitors• MAO B inhibitors

•Used as an adjuvent therapy in PD

• Both group of agents significantly reduced the "wearing off" symptoms in patients treated with levodopa/carbidopa

Dopamine and disordersof thought• Schizophrenia is a thought disorder characterized by one or more episodes of psychosis (impairment in reality testing). • Patients may manifest disorders of perception, thinking, speech, emotion, and/or physical activity.

• The most common model that explains Psychosis is the Dopamine hypothesis:• There is increase in the levels of Dopamine• D2 receptor upregulation

•Negative symptoms and positive symptoms

Dopamine antagonists in schizophreniaAntipsychoticTypical

Mechanism of action

toxicity

Phenothiazines:-chlorpromazine-fluphenazine-thioridazineThioxanthenesThiothixeneflupenthixol

Blockade of D2>>5HT2A

Akathisia,Dystonia, parkinson symptom ,tardive dyskinesia, hyperprolactinemia

ButyrophenonesHaloperidolDroperidoldomperidone

Blockade of D2>>5HT2A

Extrapyrimidal dysfunction

Antipsychotic Drugs:Typical Antipsychotic Agents:Chlorpromazine( 1954) and related drugs:• Affinity binding studies performed demonstrated that both therapeutic efficacy and extrapyramidal adverse effects of the typical antipsychotics correlate directly with the affinity of these drugs for D2 receptors.• Antipsychotics appears to involve antagonism of mesolimbic, and possibly mesocortical, D2 receptors.•Helpful in controlling positive symptoms than negative symptoms

Adverse effects:Many of the adverse effects of the typical antipsychotics are likely mediated by binding of these drugs to D2 receptors at different sites•Basal ganglia (nigrostriatal pathway)• Extrapyramidal effects• Neuroleptic malignant syndrome (NMS): actions of the

antipsychotics on the dopaminergic systems in the hypothalamus.• Tardive dyskinesia: The syndrome is characterized by

repetitive, involuntary, stereotyped movements of the facial musculature, arms, and trunk.

•Pituitary gland effects:• Amenorrhea, Galactorrhoea

• All of these drugs are more effective than the typical antipsychotics at treating the “negative” symptoms of schizophrenia

• Antagonist action at both 5-HT 2 and selective D4 antagonism• Better tolerability and safety profile

AntipsychoticAtypical

Mechanism of action toxicity

AripiprazoleClozapineOlanzapineQuetiapineRisperidoneZiprasidone

Blockade of 5HT2A>D2 Agranulocytosis(Clozapine),Weight gain, low seizure threshold, cataract, QT prolongation

Atypical Antipsychotics

Dopamine and prolactin secretion

• Tubulo-infundibular pathway regulates prolactin secretion

•Hyperprolactinemia is associated with pituitary tumours

• Egrot alkaloids:• Bromocriptine and cabergoline are potent D2 receptor agonist and a weak D1 antagonist used for the treatment of hyperprolactinemia

Dopamine and Drug addiction• Cocaine, substituted amphetamines,  MDMA(ecstasy) and other psychostimulants exert their effects primarily or partly by increasing dopamine levels in the brain

The effects of psychostimulants include increases in heart rate, body temperature, and sweating; improvements in alertness, attention, and endurance; increases in pleasure produced by rewarding events; but at higher doses agitation, anxiety, or even loss of contact with reality

Dopamine and ADHD• Potential therapeutic benefits of the selective D4 agonist, A-412997, in cognitive tasks and animal models of ADHD

Dopamine in emergency•Dopamine is a catecholamine sympathomimetic with both direct and indirect effects

Dose Effectat low infusion rates (about 2 micrograms/kg perminute

Dopamine differs from adrenaline and noradrenaline in dilating renal and mesenteric blood vessels and increasingurine output

At slightly higher infusion rates (around 2 to10 micrograms/kg per minute)

This effect is predominantit also stimulates beta1-adrenergic receptors in the myocardium,

Even higher 10 to 20 micrograms/kg per minute

the effects of alpha adrenergicstimulation, vasoconstriction predominate

Dopamine and Emesis:

•Metoclopramide & DomperidoneThese are prokinetic drugs which causes blockage of D2 receptors in CTZ and Periphery:• Antiemetic• Hasten esophageal clearance.• Increase tone of the gastro-esophageal sphincter.• Accelerate gastric emptying.

• Butyrophenones(Chlorpromazine and others) are antipsychotic agents with significant D2 receptor blockage activity used for the treatment of Emesis.