Neuroleptics

Neuroleptics

• drugs used in management of psychosis

• antipsychotics

• divided into typical and atypical agents

  • typical: older

  • atypical: newer, fewer extrapyramidal effects

Dopamine hypothesis

schizophrenia is caused by increased and dysregulated levels of DA neurotransmission in brain

Dopamine pathway functions

• reward (motivation)

• pleasure/euphoria

• motor function (fine tuning)

• compulsion

• perseveration

Serotonin pathway functions

• mood

• memory processing

• sleep cognition

Types of Dopamine receptors

• D1 receptor family

  • promote cAMP

  • promote PIP₂ hydrolysis

• D2 receptor family

  • decrease cAMP

  • increase K+ currents

  • decrease voltage-gated Ca2+ currents

Typical antipsychotics

• D2 receptor antagonists

• haloperidol (high potency)

MOA of typical antipsychotics

• block D2 receptors in all of the CNS dopaminergic pathways

  • prevent dopamine being used

  • reduce dopamine

• antagonism of mesolimbic, and possibly mesocortical, D2 receptors

Tardive Dyskinesia

• side effect of antipsychotics

• observed most frequenty after prolonged treatment with drugs that have a high affinity for D2 receptor, like haloperidol

• repetitive, involuntary, stereotyped movements of facial musculature, arms, trunk

Neuroleptic malignant syndrome (NMS)

• most severe adverse effect of the typical antipsychotics

• rare but life-threatening

• catatonia, stupor, fever, autonomic instability, myoglobinemia

• death occur in about 10% of cases

• most commonly associated with typical antipsychotic drugs that have a high affinity for D2 receptors, like haloperidol

Atypical psychotics

• D2 receptor antagonists (low potency)

• Clozapine

• Olanzapine

MOA of atypical antipsychotics

• relatively low affinity for D2 receptors

• antagonist action at both 5-HT₂ and D2 receptors

• rapid D₂ dissociation

• 5-HT1_1A agonism

5-HT₂ hypothesis

antagonist action at the serotonin 5-HT₂ receptor or antagonist action at both 5-HT₂ and D2 receptors is critical for the antipsychotic effect of atypical antipsychotics

Side effects of atypical antipsychotics

• significantly milder extrapyramidal symptoms than typical antipsychotics

• higher incidence of metabolic dysfunction, weight gain, sedation

Parkinson’s disease

• selective loss of dopaminergic neurons in substantia nigra pars compacta

  • at least 70% neurons destroyed when symptoms appear

• results in bradykinesia (slow movement), rigidity, impaired postural balance

• characteristic tremor when limbs at rest

Why is carbidopa administered with levodopa for parkinson’s disease treatment?

carbidopa is an AADC inhibitor that blocks the peripheral metabolism of levo-dopa, allowing more levo-dopa in the brain that can be converted into dopamine

what enzymes metabolize L-Dopa in PNS?

• aromatic l-amino acid decarboxylase (AADC)

• catechol-o-methyltransferase (COMT)

Can carbidopa cross the blood-brain barrier?

No

How do entacapone and tolcapone increase the fraction of levodopa available to the brain?

• inhibit COMT in periphery

What enzyme transports L-DOPA across the blood-brain barrier?

L-neutral amino acid transporter (LNAA)

What metabolizes L-DOPA to dopamine in the brain?

AADC

Major limitation to use of dopamine receptor agonists

• tendency to induce unwanted adverse effects (nausea, peripheral edema, hypotension)

• may produce excessive sedation, vivid dreams, hallucinations (esp in elderly)

• may also impair impulse control (gambling, overspending, compulsive eating)