Extrapyramidal Symtpoms

Question 1

EPS Pathways

Answer 1

1st-generation antipsychotics are D2 antagonists

1. Mesocoritcal pathway: secondary negative symptoms
   Research on schizophrenia pathophysiology suggests that a dysfunction of this pathway is associated with cognitive impairments and disturbances of emotions and affect (negative symptoms). Blockade of the mesocortical pathway by high doses of first-generation antipsychotics can induce secondary negative symptoms and cognitive effects.
2. Mesolimibic pathway: antipsychotic effects (primary pathway that we get what we want from antipsychotics)
   overactivity of this pathway is thought to be involved in the pathophysiology of positive symptoms of schizophrenia. Blockade of D2 receptors in the mesolimbic pathway has been proposed as a possible mechanism of antipsychotic action of first-generation agents.
3. Nigrostriatal pathway: extrapyramidal symptoms (cause of parkinsonism symptoms as well)
   Antagonism of D2 receptors in the nigrostriatal pathway is associated with increased risk of extrapyramidal symptoms
4. Tuberoinfidibular pathway: hyperprolactinemia
   Hyperprolactinemia; Dopamine acts as prolactin-inhibiting factor, D2 blockade increases prolactin levels by promoting its release in the pituitary gland.

Question 2

Extrapyramidal Symptoms (antipsychotics reduce dopamine)

Answer 2

Extrapyramidal means outside pyramidal (not pyramidal). Coordinates motor activity without innervating motor neurons.
. EPS resembles Parkinson’s disease.
. Long-term exposure can cause tardive dyskinesis which resembles Huntington’s disease.

1. Dystonia: muscle spasms/cramping, esp neck/shoulders
2. Akathesia: restless agitation
3. Parkinsonian symptoms: jerky movements, shuffling
4. Tardive dyskinesia: involuntary facial movements (develops later – months to years)

Question 3

Oculogyric Crisis

Answer 3

describes the clinical phenomenon of sustained dystonic, conjugate and typically upward deviation of the eyes lasting from seconds to hours.

Question 4

Cortico-Striato-Thalamo-Cortical Loop

CSTC Loop

Answer 4

s far as we know, it’s not a cure right now but, but it does treat tardive dyskinesia and to understand that we have to understand how movement happens in the quarter goes straight up the lambo cortical loop the CS TC loop the CS TC loop, is something that we talked about a lot in anxiety.

CSTC has a role in movement.

There is a diret pathway and an indirect pathway.

The direct pathway:

The indirect pathway goes through the dorsal striatum

 a. In the spiny neuron there's a little dopamine2 receptor and it is called a stop pathway.
 b. So when dopamine is available domain inhibits the STOP pathway, and that allows us, as it goes up to the cortex allows us to move (GO)
        i. We can we can go normally when dopamine antagonist or a dopamine2 partial agonist is given.
        ii. Then what happens is the D2 Blocker activates the STOP pathway, and it causes drug induced Parkinsonism because it says stop don't go.
        iii. Then you get the PD shuffle.
c. Chronic blockade of this enhances inhibition of the STOP pathway and then get involuntary hyperkinetic motions.

Question 5

Tetrabenazine

Answer 5

1. VMAT2 inhibitor
2. It reversibly inhibits only VMAT2
3. Although VMAT2 transports multiple neurotransmitters into synaptic vesicles (dopamine, norephinephrine, serotonin, and histamine), Tetrabenazine preferentially affects dopamine transport at clinical doses (Stahl, p. 175).
   ‘
4. When tetrabenazine related drugs block the transport of dopamine into presynaptic vesicles, dopamine is rapidly degraded by monoamine oxidase within the presynaptic neuron
   a. this leads to depletion of presynaptic dopamine proportional to the degree of VMAT2 inhibition.
5. Is an inactive prodrug converted into four active dihydro metabolites
   a. all four metabolites are inactivated by CYP450 2D6.
6. approved for use in Huntington’s Disease but not yet for TD.
7. Has a short half life and dosing is TID

8, has peak-dose side effects of sedation and parkinsonism, risk of depression and even suicide when used to treat Huntington’s Disease (Stahl, p. 175).

Question 6

Deuterated tetrabenazine (Astro)

Answer 6

1. Converts a drug that is a good substrate for CYP450 2D6 into a poorer substrate for CYP450 2D6
   a. This allows for a longer half life, less freequent dosing, and lower peak plasma levels.
   b. Take a hydrogen away and they put a heavy hydrogen there.
2. this drug gets broken down into the same things before, but the cyp4 50 doesn’t eat it up so much, and this is helpful, this is marketed as the drug astro.

Question 7

VMAT2 Inhibitors (vesicular monoamine transporters)

Answer 7

1. treats tardive dyskinesia (does not go away but VMAT2 can help).
2. When you give a VMAT2 inhibitor the pump is not bringing the dopamine into the vessel and there is less dopamine in the vessels, and that means there is dopamine depletion so there is less dopamine that gets into the synaptic cleft.
3. VMAT2- One of them inhibits the STOP and the other enhances the go in the in the striatum.
4. Too much stopewith the upregulation of the dopamine inhibitors produces TD but in the presence of VMAT2 the indirect path reduces the motor output in the cortex and it appears to have some effect on the direct pathway by reducing the Go a little bit. So less hyperkinetic movement overall.

Question 8

Neuroleptic Malignant Syndrome (FEVER) -a D2 blocker side effect

Answer 8

1. Fever
2. Encephalopathy.
3. Vital sign instability.
4. Elevated WBC and CPK
5. Rigidity.