Antipsychotics & Parkinson's Flashcards
What disease is the primary indication for the use of anti psychotics?
Schizophrenia
Describe the positive and negative symptoms of schizophrenia
Schizophrenia consists of positive symptoms such as hallucinations, delusions, disorganized thought or behavior, whereas negative symptoms of the disease are apathy, flat affect and a decrease in energy
What symptoms of shizophrenia are treated with FGA?
Only the positive symptoms
Name high potency FGA
Haloperidol, Trifluoperazine, Fluphenazine
Name low potency FGA
Chlorpromazine and thioridazine
Describe the MOA of FGA
All first generation antipsychotics work by blocking D2 receptors in the CNS, especially in the mesolimbic and striatofrontal system
What are high potency FGA associated with
Trifluroperazine and fluphenazine are high potentcy first generation antipsychotics, which means greater D2 receptor binding (lower EM50); these agents are NOT strongly associated with sedating, waking, or anticholinergic activity but confer a high risk of extrapyramidal side effects
What are low potency FGA associated with
Chloropromazine and Thioridazine are low potency (high EM50) first generation antipsychotics that are associated with low risk of extrapyramidal symptoms but have high histaminic and muscarinic activity with a corresponding increased risk of sedation and anticholinergic effects
What is the hallmark of acute psychotic episodes? What can exacerbate acute psychotic episodes?
Excess of dopamine, dopamine agonist such as levodopa
How are acute psychotic episodes managed?
Acute psychotic episodes, regardless of the underlying condition causing them, are usually managed with high potency 1st generation anti-psychotics
What is a pharmacokinetic property of FGA
are highly lipophilic -> highly tissue and protein bound with large volumes of distribution, giving them a long half-life
What other disease can be treated with FGA?
First generation antipsychotics can be useful in the management of tourettes syndrome, though other dopamine-depleters and α-blockers are more often used
What are the side effects of low potency FGA?
Systemic side effects due to blockade of muscarinic and histamine receptorsAntimuscarinic: dry mouth, hyperthermia, constipation, blurred vision, and urinary retention Anti histamin effect: cause sedation and drowsiness which may be usefulBlock alpha 1 receptors so can cause orthostatic hypotension
What is the hallmark of side effect of high potency FGA?
Extra medullary symptoms due to blockade of D2 receptors in nigro-striatal tract, this causes an excess of cholinergic activity
What drugs can be used to control extra pyramidal side effects of high potency FGA?
Benztropine, diphenhydramine due to their anti muscarinic properties, help re establish dopamine:cholinergic balance
Describe the extra pyramidal side effect
Dystonia (seen within hours; more common with young males), akathisia (restlessness w/ inability to sit still; seen within days) , and cog-wheel rigidity (seen within weeks)
What is the most important long term side effect seen wit FGA?
The most important long-term neurological side effect you need to watch out for when using antipsychotic therapy is tardive dyskinesia
Can we use levodopa to balance out the extra pyramidal side effects instead of using anti muscarinic drugs?
Extrapyramidal Effects due to first generation antipsychotics cannot be treated with levodopa (Dopamine), as too much Dopamine is what we are trying to treat in the first place (their psychosis)
What is another AE due to central D2 receptor blockade
HyperprolactinemiaThe hypothalamus usually secretes dopamine to inhibit prolactin release from the anterior pituitary. Any drugs that block dopamine receptors will block dopamine secretion by the hypothalamus, causing hyperprolactinemia which can cause galactorrhea, amenorrhea, and impotence. Impotence and loss of libido in men due to hyperprolactinemia is due to prolactin inhibiting GnRH release from the anterior pituitary.
CV AE of FGA?
Can cause torsades
What are 2 other CNS diseases caused by FGA?
FGA reduce the threshold for seizuresAll antipsychotics (especially first generation) can cause neuroleptic malignant syndrome (NMS) which occurs to patients who are extra-sensitive to extrapyramidal side effects
What is a side effect of Chlorpromazine specifically
corneal deposits
What is a side effect of Thioridazine specifically
Retinal deposits. Deposits in the retina can cause browning of the vision and advanced cases may look like retinitis pigmentosa
Name SGA
“Quiet please, Only whispering is Appropriate” = Quetiapine, Olanzapine, Risperidone, and Aripiprazole”zipper” - ziprasidone”closet” - clozapine - the prototypical atypical antipsychotic
MOA of SGA
Second generation antipsychotics work by blocking D2 receptors in the CNS, but the key factor in the mechanism of action of second generation antipsychotics is 5-HT 2A serotonin blockade
What does blocking serotonin do in CNS
Blocking serotonin receptors modulates the release of all kinds of CNS neurotransmitters like dopamine, NE, glutamate, GABA and ACh. We just need to remember that SGA have more potent 5HT2A blockade and less potent D2 receptor blockade
Compare and contrast the AE of FGA with SGA, how are similar and different?
Anit histamine properties, anti cholinergic properties though SGA are less likely to cause this and SGA just like FGA cause orthostatic hypotension by alpha 1 blockade
What is unique about SGA in treatment of schizophrenia which is not done by FGA
Schizophrenia consists of positive symptoms such as hallucinations, delusions, disorganized thought or behavior, whereas negative symptoms of the disease are apathy, flat affect and a decrease in energy. SGA can treat negative and positive both whereas FGA only treats the positive symptoms of schizophrenia
What SGA has the highest incidence of anti muscarinic effect?
Clozapine, other second generation antipsychotics have little-to-no anti-muscurinic activity
What is a specific use of risperidone
Helpful in the management of Tourette’s syndrome, although clinically other drugs are used to treat/manage Tourette’s syndrome.
What unique AE are there for SGA that are not associated with FGA
Metabolic side effects such as includes weight gain, dyslipidemia, and diabetes
Which SGAs have the highest incidence of metabolic AE? Which one has the lowest?
Clozapine and Olanzapine carry the highest risk of metabolic side effects, while Ziprasidone carries the lowest risk for metabolic side effects
What are the unique AE of clozapine
Neutropenia and a potentially life-threatening agranulocytosis, have to monitor absolute neutrophil count in patientsClozapine is associated with a potentially fatal myocarditis and cardiomyopathy, most often in the first few months of treatment. Clozapine is known to lower the seizure threshold, precipitating seizuresThis is in addition to the metabolic and anti cholinergic side effects of clozapine
Does SGA have increased or decreased risk of seizures as compared to FGA?
Increased as compared to FGAs
What is the defining feature of SGA that makes them more useful than FGA?
Reduced incidence of extrapyramidal symptoms. Though second generation antipsychotics are less likely to have extrapyramidal symptoms, it is still possible to have them
What SGA has the highest risk of extra pyramidal side effects?
Risperidone
What increased extra pyramidal AE are associated with Risperidone
Elevated prolactin levels and neuroleptic malignant syndrome
CV AE of SGA
Can cause Torsades by prolonging QT interval
What is the treatment of Parkinson’s disease?
L dopa
What enzyme converts L dopa to dopamine in the periphery?
DOPA decarboxylase
What is the cause of adverse effects of levodopa?
Peripheral conversion to dopamine by DOPA decarboxylase
What are the AE of levodopa in the periphery and in CNS?
Acute effects due to peripheral conversion of Levodopa into Dopamine include Nausea/vomiting, cardiac arrhythmias, and orthostatic hypotensionToo much L-Dopa conversion into dopamine in the CNS can cause acute neuropsychiatric adverse effects such as agitation, anxiety, insomnia, confusion, and hallucination
Explain the fluctuations in response to levodopa in Parkinson’s disease
Fluctuations in response to L-Dopa therapy occur more frequently with chronic L-Dopa use, resulting in an off-on phenomenon (periods of akinesia alternate with periods of improved mobility, unrelated to actual dose)
How does response to levodopa change as the Parkinson’s disease progresses
The therapeutic window of L-Dopa therapy narrows as Parkinson’s progresses, leading to an unpredictable response to therapy Chronic L-Dopa therapy can cause dyskinesias (choreoathetosis of the face and distal extremities)
What is carbidopa
peripheral DOPA carboxylase inhibitor, increases the bioavailability of Levodopa for the CNS
What are the effects of taking carbidopa with levodopa
Carbidopa decreases peripheral side effects of levodopa therapy but exacerbates neuropsychiatric side effects since more of it goes to the brain
What is COMT
Catechol-O-methyltransferase works to inactivate/break-down L-Dopa by converting it into 3-O-methyldopa (3-OMD) BOTH centrally and peripherally
Name COMT inhibitors and their site of action
Tolcapone is a peripheral and central COMT inhibitor that increases the bioavailability of levodopa. Entacapone is a peripheral COMT inhibitor that increases the bioavailability of levodopa.
Why do we use entacapone more often?
Tolcapone can cause increased liver enzymes and has even been associated with hepatic failure. Due to this reason entacapone is used more often.
What another drug can be used to increase the availability do dopamine in the CNS
Selegiline can be used to treat Parkinson’s by inhibiting MAO-B, increasing dopamine levels in the CNS MAO-B (monoamine oxidase-B) selectively metabolizes dopamine
Name D2 agonists and a D3 agonist
Cabergoline and Bromocriptine are ergot alkaloids used for treating prolactinomaRopinirole is a D2 receptor agonist Pramipexole is a D3 domapine receptor agonist
What are the uses of Pramipexole and Ropinirole
Both have important roles as 1st-line monotherapy for the treatment of Parkinson’s as we want to delay the use of levodopa as much as we can to prevent AE associated with fluctuations in response to levodopa
What is another use of Pramipexole and Ropinirole.Describe this disease.
Ropinirole and Pramipexole are 1st line treatment options for restless leg syndrome (RLS) which is a disease where people have the urge to move their legs and walking and stretching resolves this urge, RLS can cause delayed on set of sleep at night
When do we add levodopa with Pramipexole and Ropinirole?
Can be added onto Levodopa therapy to help control end-of-dose akinesia and off-on phenomenon
What are the unique side effects of dopamine agonists
Rock and roll lifestyle: gambling, compulsive shopping, and hypersexuality
What are the similar side effects of dopamine agonists as levodopa?
GI upset, cardiac arrhythmias, and neuropsychosis
Amantadine
Antiviral for influenza but is also known to have dopaminergic activity. Amantadine likely enhances the effect of endogenous dopamine by increasing dopamine synthesis & release while also inhibiting its re uptake.Amantadine can be used to aleviate some of the motor symptoms of Parkinson’s disease but is less effective than Levodopa and its effects are short-lived.
What is the role of anti muscarinics in Parkinson’s disease
Help to maintain dopamine:ACh balance on the basal ganglia, can improve tremor and rigidity of Parkinson’s but has no effect on bradykinesia
Name anti muscarinics that can be used in Parkinson’s
Trihexyphenidyl and Benzotropine
What AE can be controlled by anti muscarinics
Extrapyramidal effects associated with FGA’s and SGA’s
