Pharma PA- Dopamine

Central Nervous System & Dopamine

Overview

This module focuses on dopamine, its role in Parkinson's disease, and therapeutic approaches.

Dopamine Pathways

1. Mesolimbic Pathway

   • Function: Reward, pleasure, and reinforcement learning.

   • Key Brain Regions: Ventral tegmental area (VTA) to the nucleus accumbens.

   • Clinical Relevance:

     • Addiction: Dysregulation of dopamine release leads to reinforcing effects of drugs and addictive behaviors.

     • Schizophrenia: Hyperactivity is linked to positive symptoms like hallucinations and delusions.

2. Mesocortical Pathway

   • Function: Regulates cognition, executive function, memory, and emotional response.

   • Key Brain Regions: Ventral tegmental area (VTA) to the prefrontal cortex.

   • Clinical Relevance:

     • Schizophrenia: Hypoactivity is associated with negative symptoms and cognitive deficits, such as lack of motivation.

     • Depression: Dysregulation may contribute to cognitive and emotional symptoms.

3. Nigrostriatal Pathway

   • Function: Controls motor function and coordination.

   • Key Brain Regions: Substantia nigra to the striatum (caudate nucleus and putamen).

   • Clinical Relevance:

     • Parkinson's Disease: Degeneration of dopaminergic neurons leads to motor symptoms like tremors, rigidity, and bradykinesia.

     • Huntington's Disease: Involvement in movement disorders and chorea.

4. Tuberoinfundibular Pathway

   • Function: Regulates prolactin release from the anterior pituitary gland.

   • Key Brain Regions: Hypothalamus (arcuate nucleus) to the pituitary gland.

   • Clinical Relevance:

     • Hyperprolactinemia: Disruption can lead to elevated prolactin levels, resulting in conditions such as galactorrhea and gynecomastia. Dopamine normally inhibits prolactin secretion.

5. Thalamic Pathway

   • Function: Involved in the modulation of sensory processing and attention.

   • Key Brain Regions: Midbrain to the thalamus.

   • Clinical Relevance:

     • Schizophrenia: Altered dopamine activity is implicated in sensory gating deficits and cognitive disturbances.

     • Attention Deficit Disorders: Dysregulation may contribute to attentional deficits.

6. Periventricular Pathway

   • Function: Regulates autonomic functions and stress responses.

   • Key Brain Regions: Hypothalamus to the periventricular region.

   • Clinical Relevance:

     • Homeostasis: Plays a role in maintaining physiological balance, including blood pressure and appetite control.

     • Stress Response: Involvement in the body's response to stress and emotional regulation.

7. Incerto-Hypothalamic Pathway

   • Function: Influences sexual behavior and motivation.

   • Key Brain Regions: Zona incerta to the hypothalamus.

   • Clinical Relevance:

     • Reproductive Behaviors: Dopamine activity is crucial for normal sexual function and reproductive behaviors.

     • Sexual Dysfunction: Dysregulation can lead to issues such as decreased libido and sexual arousal problems.

8. Olfactory Bulb Dopaminergic Pathway

   • Function: Modulates olfactory processing, including the detection and discrimination of odors.

   • Key Brain Regions: Dopaminergic neurons within the olfactory bulb.

   • Clinical Relevance:

     • Parkinson's Disease: Often involves early symptoms of hyposmia due to dopaminergic dysfunction.

     • Schizophrenia: Altered olfactory perception linked to dopaminergic dysregulation.

Dopamine Network

• Gpe: globus pallidus external segment

• STN: subthalamic nucleus

• Gpi/SNr: globus pallidus internal segment/ substantia nigra pars reticulata

Parkinson's disease causes the death of dopaminergic neurons in the substantia nigra, which affects the entire dopamine network. The input to the thalamus becomes increasingly inhibitory, resulting in less stimulating signals towards the frontal cortex and muscles.

Direct / Indirect Pathway

The striatum gives rise to two sets of basal ganglia connections: the direct and indirect pathways.

Dopamine:

• Stimulates striatal neurons belonging to the direct pathway.

• Inhibits those of the indirect pathway.

This is because the two types of neuron express different dopamine receptors.

5 main types of dopamine receptor:

• D1-like and D2-like

  • Direct pathway neurons are excited by dopamine since they express D1-like receptors.

  • Indirect pathway neurons are inhibited by dopamine because they express D2-like receptors.

Direct Pathway

The internal connections of the basal ganglia work by disinhibition (release of inhibition). This happens when two inhibitory neurons are arranged in series, so that the first one inhibits the braking action of the second.

The connections of the basal ganglia work by inhibition and disinhibition.

• (A) Simple illustration of an inhibitory interaction between two nerve cells. Activity in the excitatory neuron (red) is inhibited by an inhibitory interneuron (blue).

• (B) Disinhibition (release of inhibition) occurs when two inhibitory neurons occur in sequence. In this case the excitatory neuron (red) has been released from inhibition (or ‘disinhibited’) as the neuron that was previously restraining its action has itself been inhibited. In functional terms, disinhibition is equivalent to excitation.

Direct and Indirect Pathways of the Basal Ganglia.

(A) Direct pathway: Striatal neurons belonging to the direct pathway project directly to the internal pallidum and inhibit it, thereby releasing thalamocortical neurons from inhibition. In the voluntary motor loop, the direct pathway therefore facilitates movement.

(B) Indirect pathway: Striatal neurons belonging to the indirect pathway project to the external pallidum, where they inhibit a group of neurons that would normally reduce the firing rate of the subthalamic nucleus. This means that the indirect pathway disinhibits the subthalamic nucleus and accentuates its excitation of the internal pallidum. The indirect pathway therefore reinforces the default (inhibitory) outflow of the basal ganglia and prevents unwanted movements.

Parkinson's Disease

A progressive neurological disorder of muscle movement.

Case Presentation

A 66-year-old man presents with a progressively worsening tremor in his hands for the past 6 months. The tremor is worse when he is resting and improves a little when he reaches for an object or is using his hands. He also notices difficulty initiating movement when standing up to walk, taking several small, shuffling steps before reaching his full stride. Examination reveals a fairly expressionless face, a pill-rolling-type tremor of his hands at rest, and cogwheel rigidity of his arms.

Parkinson’s Disease Definition

It is a progressive neurodegenerative disorder characterized clinically by rigidity, tremor, postural instability, and slowness of movement (bradykinesia).

The lifetime risk of Parkinson disease is 2% in men and 1.3% in women.

Parkinson’s Disease – Clinical Presentation

• A resting tremor - first noted in the hand as a pill-rolling tremor (thumb and forefinger). Can also involve the leg and lip-asymmetrically.

• Rigidity—increased muscle tone that persists throughout the range of passive movement of a joint.

• Akinesia/bradykinesia

• Postural instability—tested by “pull test.”

• Masked facies (hypomimia)— Decreased blink; often there is excess drooling.

• Gait disturbance.

• Stooped posture, decreased arm swing.

• Difficulty initiating the first step

• Micrographia, hypophonia

Nonmotor symptoms

• neuropsychiatric

• cognitive

• dysautonomia
  *These symptoms also may be subject to fluctuations during “on” vs. “off” states

Common premotor symptoms

constipation, anosmia, depression, and REM sleep behavior disorder.

Parkinson’s Disease – Diagnosis

A clinical diagnosis can be made based on a comprehensive history and physical examination. The four cardinal signs used to diagnose PD are (mnemonic = TRAP):

1. T remor (resting, typically 4-6 Hz)

2. R igidity, of the cogwheel type

3. A kinesia/bradykinesia—slowing and decrement of movement

4. P ostural instability—failure of postural “righting” reflexes leading to poor balance and falls

Bradykinesia plus at least one other sign are necessary, but all four cardinal signs do not need to be present to make a presumptive diagnosis of PD and begin treatment.

Parkinson’s Disease – Differential Diagnosis

• Multiple system atrophy: distinguishing features include early autonomic dysfunction, parkinsonism, cerebellar signs, and normal cognition.

• Dementia with Lewy bodies: parkinsonism with concomitant dementia. Patients often have early hallucinations and fluctuations in level of alertness and mental status

• Corticobasal syndrome: often begins asymmetrically with apraxia, cortical sensory loss in one limb

• Progressive supranuclear palsy: tends to have axial rigidity greater than appendicular (limb) rigidity. These patients have early and severe postural instability. Hallmark is supranuclear gaze palsy that usually involves vertical gaze (especially downward) before horizontal

• Essential tremor: bilateral postural and action tremor

Secondary (acquired) parkinsonism:

1. Iatrogenic: many, including any of the neuroleptics and antipsychotics. The high-potency D_2-blocker neuroleptics are most likely to cause parkinsonism. Quetiapine is an atypical antipsychotic with lower risk of parkinsonism. Metoclopramide can also cause parkinsonism. Abuse of methamphetamine has been linked to risk of PD

2. Postinfectious parkinsonism: von Economo encephalitis

3. Chronic traumatic encephalopathy: parkinsonism and dementia after repeated head trauma

4. Toxins: (e.g., manganese, carbon monoxide)

5. Cerebrovascular disease: “vascular parkinsonism” (basal ganglia infarcts); often lower limbs (especially gait) affected more than upper extremities

Parkinson’s Disease – Imaging

Images obtained using single photon emission computed tomography (SPECT) with the radioactively labelled (^{123}I) beta-CIT.

Functional imaging of dopamine transport in Parkinson's disease:

• (A) Axial section through the basal ganglia showing the normal pattern of uptake in a healthy control. The characteristic ‘comma’ shape of the striatum (caudate nucleus and putamen) is seen.

• (B) In a patient with Parkinson's disease, there is markedly reduced signal in the putamen but not in the head of the caudate nucleus, creating a ‘full stop’ appearance.

Etiology

Cell death→↓dopamine release in the neostriatum Lost inhibitory effect of dopamine →↑Ach production → abnormal signaling= impaired mobility

Parkinson’s Disease – Pathogenesis

Progressive degeneration of the dopaminergic neurones of the substantia nigra

Inhibitory dopaminergic activity of the nigrostriatal pathway is reduced (20%–40%) in people with Parkinson disease

↓inhibitory dopaminergic activity → unopposed cholinergic neuron hyperactivity

Symptoms of parkinsonism appear only when more than 80% of the dopaminergic neurons of the substantia nigra have degenerated.

Parkinson’s Disease Therapy – Levo - Dopa

Mechanism of action

l-dopa is the immediate precursor of dopamine

able to penetrate the blood–brain barrier

l-dopa is decarboxylated to dopamine in the brain by dopa decarboxylase,

effects produced through the actions on D_2 receptors

Levodopa has an extremely short half-life (1 to 2 hours) → fluctuations in plasma concentration →fluctuations in motor response → give rise to the more troublesome "on-off" phenomenon

Levo - Dopa, Adverse Effects

Peripheral metabolism→ large doses are needed to produce therapeutic effects in the brain → ↑side effects

• Nausea and vomiting - by stimulation of dopamine receptors in the chemoreceptor trigger zone in the area postrema

• Psychiatric side effects (schizophrenia-like symptoms) - vivid dreams, confusion and psychotic symptoms - effects are probably a result of increased dopaminergic activity in the mesolimbic area of the brain

• Cardiovascular effects, cardiac arrhythmias are caused by increased catecholamine stimulation following the excessive peripheral metabolism of l -dopa to noradrenaline.

• Dyskinesias - involve the face and limbs. They usually reflect overtreatment and respond to simple dose reduction.

Parkinson’s Disease – Therapy

Levodopa therapy:

The most efficacious treatment and cornerstone of symptomatic therapy

Used in combination with carbidopa (peripheral dopa decarboxylase inhibitor) →minimizes side effects (nausea, light-headedness, postural hypotension).

starting dose is 25/100 mg (carbidopa/levodopa) 2 times a day 1 hour before meals

Parkinson’s Disease – Carbidopa

Carbidopa - dopamine decarboxylase inhibitor

↓metabolism of levodopa in the periphery

Addition of carbidopa lowers the dose of levodopa needed by four- to five-fold (↓adverse effects)

Levodopa-carbidopa reduces the severity of symptoms for the first few years of treatment

A decline in response during the 3rd to 5th year of therapy.

Parkinson’s Disease – COMT Inhibitors

methylation of levodopa by COMT

When peripheral dopamine decarboxylase activity is inhibited by carbidopa →3-0-methyldopa is formed that competes with levodopa for active transport into the CNS

Entacapone and tolcapone - selectively and reversibly inhibit COMT

↓ plasma concentrations of 3-0-methyldopa →↑central uptake of levodopa → ↑concentrations of brain dopamine.

Both ↓ symptoms of "wearing-off" phenomena

Adverse effects: diarrhea, postural hypotension, nausea, anorexia, dyskinesias, hallucinations, and sleep disorders.

Parkinson’s Disease – Dopamine Receptor Agonists

Dopamine receptor agonists -not as potent as levodopa

Used as initial treatment in younger patients in an attempt to delay the onset of complications (dyskinesias, motor fluctuations) associated with levodopa therapy.

1. Bromocriptine- ergot derivative → hallucinations, confusion, delirium, nausea, and orthostatic hypotension are more common, whereas dyskinesia is less prominent

2. Apomorphine, pramipexole, ropinirole, and rotigotine

Apomorphine is used for acute management of the hypomobility "off" phenomenon in advanced Parkinson disease.

Rotigotine is administered as a once-daily transdermal patch that provides even drug levels over 24 hours. These agents alleviate the motor deficits in patients who have never taken levodopa and also in patients with advanced Parkinson disease who are treated with levodopa.

Dopamine agonists may delay the need to use levodopa in early Parkinson disease and may decrease the dose of levodopa in advanced Parkinson disease.

Parkinson’s Disease – MAO - B Inhibitors

Selegiline- selectively inhibits monoamine oxidase (MAO) type B (dose-dependent), the enzyme that metabolizes dopamine.

↓metabolism of dopamine → selegiline ↑dopamine levels in the brain

enhances the actions of levodopa and substantially reduces the required dose.

Selegiline is metabolized to methamphetamine and amphetamine → stimulating→ insomnia

Rasagiline - irreversible and selective inhibitor of brain MAO type B, has five times the potency of selegiline.

Parkinson’s Disease – Amantadine

Amantadine-antiviral drug

An extended-release version is now FDA approved for the treatment of dyskinesia.

Amantadine has several effects on neurotransmitters implicated in parkinsonism:

• increasing the release of dopamine

• blocking cholinergic receptors

• inhibiting the N-methyl-c-aspartate (NMDA) type of glutamate receptors.

Amantadine is less efficacious than levodopa, and tolerance develops more readily.

Parkinson’s Disease – Therapy

Trihexyphenidy and Benztropine

• Anticholinergic agents are only helpful in treating tremor but may be more effective than levodopa for tremor in some circumstances.

• They can also be used to treat drooling in patients with PD.

• Potential side effects include constipation, urinary retention, memory impairment, and hallucinations.

• They should be avoided in the elderly.

Levo - Dopa - Strategies

3 strategies to optimize l -dopa treatment → maximize the central effects of l -dopa within the brain and minimize its unwanted peripheral effects.

1. Carbidopa or benserazide, inhibitors of dopa decarboxylase in the periphery that cannot penetrate the blood–brain barrier. Hence, extracerebral conversion of l -dopa to dopamine is inhibited.

2. Domperidone, a dopamine antagonist, that does not penetrate the blood–brain barrier and can, therefore block the stimulation of dopamine receptors in the periphery.

3. Selegiline and entacapone, monoamine oxidase (MAO B ) and catechol- O -methyltransferase (COMT) inhibitors, respectively, which inhibit dopamine metabolism in the CNS.

Parkinson’s Disease – Therapy

Treatment of nonmotor symptoms:

-as depression, anxiety, irritability, dementia, psychosis, urinary and sexual dysfunction, sleep disturbances often cause a great deal of distress for patients and caretakers alike. Treatable symptoms should be addressed pharmacologically using medications appropriate for elderly patients sensitive to antidopaminergic medications.

Psychosis:

Dopamine agonists and anticholinergics can cause hallucinations, so adjustment of these medication should be the first step.

Pimavanserin is FDA approved for the treatment of Parkinson disease psychosis and has been shown effective for the treatment of hallucinations and delusions associated with Parkinson disease psychosis.The medication is an inverse agonist of 5-HT2A and 5-HT2C receptors without any evidence of dopamine blockade.

Parkinson disease dementia:

Rivastigmine, a cholinesterase inhibitor available both orally and transdermally as a patch (with few GI side effects), is approved to treat not only Alzheimer disease but also Parkinson disease dementia.

Parkinson’s Disease – Therapy - Surgical Options

• Pallidal (globus pallidus interna) and subthalamic deep-brain stimulation (subthalamic nucleus) are currently the surgical options of choice for patients with advanced PD; similar improvement in motor function and adverse effects have been reported after either procedure.

• Focused ultrasound (FUS) is an imaging-guided method for creating therapeutic lesions in dead-brain structures including the subthalamic nucleus.

• Surgery is often limited to patients with disabling, medically refractory problems, and patients must still have a good response to l -dopa to undergo surgery.

• DBS results in decreased dyskinesias, fluctuations, rigidity, and tremor.

QUESTION

Carbidopa reduces which of the following?

A. The activity of dopa-decarboxylase in the CNS
B. The L-dopa dose necessary to achieve a therapeutic effect
C. The severity of L-dopa-associated dyskinesias
D. The time to onset of L-dopa’s therapeutic effects

Answer

B. Carbidopa, which does not penetrate the brain, reduces peripheral dopa-decarboxylase activity, and the metabolism of L-dopa. The therapeutic effect of L-dopa can be achieved at a lower dose than would be possible without carbidopa.

QUESTION

Which of the following is the most common limiting adverse effect of L-dopa?

A. Depression
B. Dyskinesia
C. Nausea
D. Orthostatic hypotension

Answer

B. The most common limiting adverse effect of L-dopa is dyskinesia that may occur in up to 90 percent of patients. Orthostatic hypotension, depression, and nausea are also adverse effects, but can be more readily managed and tolerated by patients

QUESTION

Entacapone inhibits which of the following?

A. Dopamine D_2 receptors
B. COMT
C. Monoamine oxidase B
D. Muscarinic cholinoreceptors

Answer

B. Entacapone (and tolcapone) inhibits COMT. Selegiline inhibits monoamine oxidase B. Muscarinic cholinoreceptors are inhibited by biperiden and benztropine among others. Blockade of dopamine D_2 receptors would exacerbate the symptoms of Parkinson disease

CASE

A 72 year-old man attends the emergency department following a fall. He reports that whilst walking from the living room to the kitchen, he tripped on the corner of the rug and fell forwards onto his knees. He denies sustaining any head injury but does complain of pain over his left wrist. This is his third hospital attendance with a fall in the past month. He has no significant past medical history and takes no regular medications. The patient is a retired painter and decorator, he lives alone and has no package of care. He does not drink alcohol regularly and is an ex-smoker with a 30-packyear history.

Examination

The patient is alert and orientated to time, place and person. He has no visible injuries. Cardiovascular, respiratory and abdominal system examinations are unremarkable. Neurological examination identifies bilateral increased tone in the upper limbs with a pronounced resting tremor, consistent with cogwheel rigidity. There is a slow, rhythmic `pill-rolling' tremor in the left hand. The patient's face appears expressionless, or 'mask-like’ and his speech is monotonous. He walks with a shuffling gait.

Questions

1. This patient is likely to have an underlying diagnosis of Parkinson's disease. Why should you prescribe levodopa, rather than dopamine, to this patient?

2. Are there any additional medications that can be prescribed to enhance the efficacy of levodopa?

3. Would you change the treatment if the patient would have been a young, 55-year-old patient?

Answers

1. Movement control is governed by multiple, complex neural pathways working in tandem. One such pathway involves neurons located within the substantia nigra, in the ventral midbrain that communicate with the basal ganglia via the neurotransmitter, dopamine. Parkinson's disease develops when there is degeneration, of dopamine-producing cells in the substantia nigra, resulting in reduced levels of dopamine available for neurotransmission. Exogenous dopamine can be administered to patients, however dopamine is water-soluble and hydrophilic and thus unable to cross the blood—brain barrier. Levodopa, a dopamine pro-drug, is able to cross the blood—brain barrier via an amino acid transport system, where it is then converted to dopamine.

2. When administered orally, levodopa is absorbed by the gastrointestinal tract and converted to dopamine by a dopa decarboxylase (DDC) inhibitor. To prevent conversion to dopamine occurring in the periphery (thus requiring larger doses to be administered and inducing greater adverse effects), levodopa is combined with a peripheral dopa decarboxylase inhibitor, such as carbidopa. Peripheral DDC inhibitors are unable to cross the blood-brain barrier, enabling levodopa to be transported to the brain, where it is then converted to dopamine. Levodopa is also metabolised to 3- 0-MDopa by the catechol- 0 –methyltransferase (COMT) enzyme. COMT inhibitors, such as tolcapone and entacapone, can reduce the peripheral breakdown of levodopa

Questions

Which pathway is involved in the reward pleasure and reinforcement learning functions?
A. Nigrostriatal Pathway
B. Mesolimbic Pathway
C. Tuberoinfundibular Pathway
D. Thalamic Pathway

Degeneration of dopaminergic neurons in which brain region is primarily responsible for Parkinson’s disease?
A. Prefrontal cortex
B. Ventral tegmental area
C. Substantia nigra
D. Hypothalamus

What is a common early symptom of Parkinson's disease associated with olfactory dysfunction?
A. Hyposmia
B. Dyskinesia
C. Bradykinesia
D. Akinesia

Questions

Which clinical feature is NOT typically associated with Parkinson’s disease?
A. Pill-rolling tremor
B. Cogwheel rigidity
C. Hyperactivity
D. Bradykinesia

What is the primary mechanism of action for Levodopa in treating Parkinson’s disease?
A. Direct dopamine receptor agonist
B. Inhibition of monoamine oxidase
C. Precursor of dopamine that crosses the blood-brain barrier
D. COMT inhibitor

Which of the following drugs is used in combination with Levodopa to minimize its side effects?
A. Pramipexole
B. Selegiline
C. Carbidopa
D. Tolcapone

Questions

Which adverse effect is most commonly associated with long-term use of Levodopa?
A. Hypertension
B. Dyskinesia
C. Hyperprolactinemia
D. Hypotension

What is the function of COMT inhibitors like Entacapone in the treatment of Parkinson’s disease?
A. Increase dopamine levels by inhibiting its breakdown
B. Inhibit peripheral metabolism of Levodopa
C. Directly stimulate dopamine receptors
D. Prevent dopamine reuptake

Which dopamine pathway is primarily associated with motor function and coordination?
A. Mesolimbic Pathway
B. Mesocortical Pathway
C. Nigrostriatal Pathway
D. Tuberoinfundibular Pathway

Central Nervous System & Dopamine - Antipsychotic Agents

Overview

This module covers dopamine, schizophrenia, and therapeutic approaches.

Case Presentation

A 19-year-old man is brought to the physician’s office by his very concerned mother. He has been kicked out of the dormitory at college for his “bizarre” behavior. He has accused several fellow students and professors of spying on him for the CIA. He stopped attending his classes and spends all of his time watching TV because the announcers are sending him secret messages on how to save the world. He has stopped bathing and will only change his clothes once a week. In your office you find him to be quiet, and unemotional. The only spontaneous statement he makes is when he asks why his mother brought him to the office of “another government spy."

Theories of the Cause of Schizophrenia

Theories:

genetic factors (monozygotic twins have 50% concordance, 17% in dizygotic twins) and environmental factors (stressful events often precede onset and influence the course of the illness).

The dopamine theory

(increased dopamine transmission):

Evidence: clinical dose of an antipsychotic is proportional to its ability to block the D_2 receptor. Psychiatric side effects are seen with drugs that increase dopaminergic transmission (L-dopa, amfetamine, bromocriptine).

Evidence against: level of dopamine metabolites in the cerebrospinal fluid (CSF) of patients is normal or low. → dopamine is not the only factor causing symptoms

The developmental theory

(disordered development):

Evidence : patients show reduced temporal lobe size compared with controls.

Evidence against: not all studies agree on these findings and the theory does not explain the efficacy of neuroleptic drugs.

Antipsychotic Drugs

The antipsychotic drugs

1. first- generation = typical , traditional

2. second-generation = atypical

1) first-generation → “low potency” VS “high potency.” –Classified based on affinity for D_2 receptor. HALOPERIDOL , CHLORPROMAZINE

→ competitive inhibitors of dopamine D_2 receptors -more likely to be associated with movement disorders known as extrapyramidal symptoms (EPS).

High Potency Antipsychotics

haloperidol relative receptor affinities

DA D_2:

psychosis

bradykinesia
concentration

Dopamine Pathways

Mesolimbic:

↑ psychosis too much dopamine = positive symptoms of schizophrenia

nigrostriatal
extrapyramidal system
low DA leads to Parkinson's basal ganglia
high DA leads to dyskinesias

mesocortical
low DA leads to negative syndroms of schizophrenia

mesolimbic
high DA leads to positive syndroms of schizophrenia ventral tegmentum substantia nigra nucleus accumbens

Dopamine Pathways

Mesocortical
↓ concentration
social withdrawal
too little dopamine = negative symptoms of schizophrenia
Psychosis
bradykinesia
prolactin
risk of NMS

Dopamine Pathways-Nigrostriatal

Signs & Symptoms:

• oculogyric crisis

• torticollis

• laryngeal dystonia

Pathophysiology

• Dopamine ↓↓

• Acetycholine ↑↑

Treatment

• Anticholinergics

Dopamine Pathways-Nigrostriatal

Akathisia

• restlessness

• anxiety

• pacing

Beta-blockers, anti-psychotics

Dopamine Pathways-Nigrostriatal

Pseudoparkinsonism Symptoms:

• mask-like faces

• drooling

• tremors

• pillrolling motion

• cogwheel rigidity

• shuffling gait

After treatment with anticholinergics

Dopamine Pathways - Nigrostriatal

Tardive dyskinesia →Result of chronic D2 receptor antagonism in the nigrostriatal tract →up-regulation of post-synaptic D2 →increase in psychotic symptoms to which the clinician increases the dose of the antipsychotic More receptors are blocked, but the post-synaptic neuron is thought to develop "super-sensitivity" to any dopamine that is present in the synapse.

Antipsychotic Drugs

2) Second-generation antipsychotic drugs - lower incidence of EPS

• higher risk of metabolic side effects (diabetes, hypercholesterolemia, and weight gain)

→activity: blockade of both serotonin and dopamine +/-other receptors.

1. first-line therapy → schizophrenia

2. Refractory patients: 10% to 20% of patients with schizophrenia have an insufficient response to all first- and second-generation antipsychotics. → clozapine-effective, but presents serious adverse effects:bone marrow suppression, seizures, and cardiovascular side effects, such as orthostasis, agranulocytosis → monitoring of white blood cell counts.

Atypical Antipsychotics

Clozapine:

constipation
sedation
dry mouth
weight gain
confusion
orthostatic hypotension
dizziness

Second Generation:

concentration
psychosis
ici bradykinesia
prolactin concentration

Antipsychotic Drugs – Mechanism of Action

Dopamine antagonism

All first-generation + second-generation antipsychotic drugs block D_2 dopamine receptors in the brain and the periphery

Serotonin receptor–blocking activity:

(mainly second-generation) inhibition of serotonin receptors 5- HT2A receptors.

• Clozapine -affinity for D1, D4, 5-HT2 , muscarinic, and -adrenergic receptors, weak dopamine D_2 receptor antagonist

• Risperidone blocks 5-HT2A receptors to a greater extent than it does D_2 receptors

• Aripiprazole

• Pimavanserine- indicated for psychosis associated with Parkinson disease

Antipsychotic Drugs – Actions

The clinical effects blockade at dopamine and/or serotonin receptors.

Antipsychotic effects: reduce hallucinations and delusions (known as “positive” symptoms)

The “negative” symptoms second-generation agents

Extrapyramidal effects: Dystonias, Parkinson-like symptoms, akathisia, and tardive dyskinesia

Antiemetic effects: mediated by blocking D_2 receptors of the chemoreceptor trigger zone of the medulla

Anticholinergic effects: chlorpromazine, clozapine, and olanzapine

Antipsychotic Drugs – Actions

Blockade of α-adrenergic receptors

→ orthostatic hypotension and light- headedness.

alter temperature-regulating mechanisms → produce poikilothermia (condition in which body temperature varies with the environment).

Pituitary → increase in prolactin release

antagonists of the H_1-histamine receptor → sedation (chlorpromazine, olanzapine, quetiapine, and clozapine)

Sexual dysfunction may occur

Antipsychotic Drugs – Therapeutic Uses

1. Treatment of schizophrenia: -only efficacious pharmacological treatment for schizophrenia.

2. Prevention of nausea and vomiting: prochlorperazine useful in the treatment of drug- induced nausea.

3. used as tranquilizers to manage agitated and disruptive behavior secondary to other disorders.

4. Chlorpromazine -to treat intractable hiccups.

5. risperidone and aripiprazole are approved for the management of disruptive behavior and irritability secondary to autism.

6. management of the manic and mixed symptoms associated with bipolar disorder.

7. aripiprazole and quetiapine - used as adjunctive agents with antidepressants for treatment of refractory depression.

Antipsychotic Drugs – Absorption and Metabolism

oral administration → variable absorption that is unaffected by food

readily pass into the brain and have a large volume of distribution.

Metabolized : by the cytochrome P450 system in the liver→ some metabolites are active and have been developed as pharmacological agents themselves

haloperidol decanoate, risperidone microspheres, paliperidone palmitate, aripiprazole monohydrate, and olanzapine pamoate are long-acting injectable (LAI) formulations of antipsychotics. → therapeutic duration of action of up to 2 to 4 weeks.

Antipsychotic Drugs – Adverse Effects

Neuroleptic malignant syndrome: This potentially fatal reaction to antipsychotic drugs is characterized by muscle rigidity, fever, altered mental status and stupor, unstable blood pressure, and myoglobinemia.

Treatment necessitates discontinuation of the antipsychotic agent and supportive therapy. Administration of dantrolene or brom