EXAM 5 Antipsychotics Dr. Pond Flashcards
Symptoms of Psychoses
-false beliefs (delusion)
-hallucinations (abnormal sensation)
-antipsychotics are not specific for the type of psychoses - only treat the symptoms of the disorder
Symptoms of Schizophrenia
(particular type of psychoses)
-positive symptoms: hallucinations and delusions
-negative symptoms (depressive symptoms):
alogia (not being verbal with others)
anhedonia (no pleasure)
avolition (not able to plan or do things)
asociality
blunted effects
-cognitive symptoms:
deficit with working memory
attention deficit
deficit with processing speed of information
Which anatomical changes are associated with schizophrenia?
-enlarged ventricles
-widening of sulci -> reflecting a reduction of cortical tissue in the frontal lobe
Which neural pathway in the brain is associated with hyperfunction? Describe the symptoms.
Mesolimbic pathway
-> Positive symptoms due to hyperactivity of Dopamine neurons: hallucinations
REMINDER: pathway of the mesolimbic pathway
VTA to nucleus accumbens
Dopamine REWARD pathway
Which neural pathway in the brain is associated with hypofunction? Describe the symptoms.
Mesocortical pathway
Loss of activation of dopamine neurons -> negative symptoms: depression, problems with working memory and attention
REMINDER: pathway of the mesocortical pathway
VTA to the prefrontal cortex
Which pathway is responsible for motor control?
nigrostriatal: nigra to caudate-putamen
Which pathway is responsible for prolactin secretion?
tuberoinfundibular
arcuate nucleus of the hypothalamus to median eminence
DA acts as the inhibiting NT for prolactin secretion
What is the effect of Dopamine antagonists on the nigrostriatal pathway?
responsible for motor function -> disorder of motor function
Parkinsonian symptoms
What is the effect of Dopamine antagonists on the tuberoinfundibular pathway?
DA inhibits prolactin
-> DA antagonist block DA -> more prolactin secretion, also disrupts fertility
What is the effect when 5-HT-2A agonists are activated and what is the MOA of atypical (new gen) antipsychotics?
Hallucinations (postsynaptic, excitatory)
5-HT2A antagonist or inverse agonist (opposite effect of agonist)
modulate release of DA in the cortex, limbic, and striatum -> there may be an interplay with the dopamine pathway
Glutamate is involved in which neuron pathway?
VTA to the prefrontal cortex
Which antipsychotics are considered “old”?
-Chlorpromazine
-Thioridazine
-Perphenazine
-Haloperidol
P*TCH
Which Dopamine receptor in the limbic system is thought to be responsible for the psychotic symptoms?
D2 receptor
older antipsychotics are mainly Dopamine antagonists -> help with positive symptoms (since hyperfunctional), less with negative symptoms (since hypofunctional and antagonist is not helpful here)
Antipsychotics also hit which receptors?
-5-HT2A -> Antagonism/inverse agonism
-block muscarinic receptors
-block alpha-adrenergic receptors
-block histamine receptors
Side effects that come with blocking different receptors
M1 muscarinic blockage:
-loss of accommodation (cant focus between near and distant object), dry mouth, difficulty urination, constipation
alpha-1 blockage:
orthostasis, impotence, failure to ejaculate
blocking antihistamine R:
weight gain, sedation
Which side effects are associated with antipsychotics?
-Infertility, impotence, amenorrhea-galactorrhea (lack of menstrual periods and increased milk production)
-sedation
Movement:
-rare neuroleptic malignant syndrome (hyperthermia)
-acute dystonia (involuntary muscle contraction- twisting movements)
-inner restlessness – RLS
-Parkinsonism
Long-term (months to years):
-Tardive dyskinesia and perioral tremor
Which drugs may help with motor dysfunctional side effects of antipsychotics?
???
Anticholinergics, drugs that naturally hits muscarinic receptors ???
-Benztropine for example
What are the key symptoms of Neuroleptic malignant syndrome?
Heat, acidosis, Rigidity
also:
-high fever
-sweating
-unstable BP
-stupor
-autonomic dysfunction
Which drugs treat Neuroleptic malignant syndrome?
Dantrolene
Repitive, involuntary, purposeless movements, often in the face
Tardive dyskinesia
15-20% with older antipsychotics
-may be irreversible
What is the BBW for antipsychotics
increased risk of death in elderly patients with dementia-related psychotics
What is the key difference between the newer atypical antipsychotics and the older ones?
higher potency at blocking 5-HT2A than D2 receptors (10x)
except for quetiapine
->less EPS (Parkinson-like) symptoms and tardive dyskinesia, little to no increase in prolactin secretion
-significant improvement in treating the negative symptoms
Which drugs are considered atypical (new gen)?
-clozapine
-risperidone
-olanzapine
-quetiapine
-aripiprazole
-lurasidone
-ziprasidone
-cariprazine
-> Significant weight gain may cause other problems like diabetes, hyperlipidemia, heart disease
What is the BBW for Clozapine (atypical)
-agranulocytosis (have to monitor WBC)
-Seizures
-orthostatic hypotension
-myocarditis, and cardiomyopathy
highly associated with weight gain
Advantage of Clozapine
it reduces the risk of suicide (which is higher in schizophrenia patients)
Which atypicals are mostly associated with weight gain?
Clozapine
Olanzapine
Which antipsychotic is associated with less weight gain?
Ziprasidone
-blockade of NE and 5-HT uptake, and
5HT1a agonism - so more 5-HT
Target of Cariprazine
High affinity for D3
D2 antagonist/partial agonist
low affinity for 5-HT2A, 5-HT2C
Which drug causes fewer EPS side effects?
Aripiprazole
because it is a partial D2 agonist, rather than a D2 antagonist like the older ones
How does the drug Samidorphan work?
mu-opioid antagonist: on the POMC neuron
POMC is a precursor for ß-endorphin and alpha-MSH
alpha-MSH binds to MC4R -> loss of appetite -> weight loss
ß-endorphin binds to MOR causing neg feedback of alpha-MSH release (we don’t want that)
Samidorphan blocks MOR AUTORECEPTORS (neg feedback) -> more release of alpha-MSH binding to MC4R -> loss of appetite
Role of Lithium in bipolar disorder
used for Bipolar disorder, has delayed onset - so used for prophylaxis rather than acute manic episodes
MOA for Lithium
-Substitutes for Na+ -> effects on electrolytes and ion transport
-Increases GABA inhibition, decreases NMDA excitation
-inhibits DAergic neurotransmission
-also affects second messenger and intracellular enzymes after NT hits the receptor
Which enzymes are blocked by Lithium?
-Inositol monophosphatase
-Inositol polyphosphate 1-phosphatase
->thereby blocking the inositol recycling (conversion of IP2 to IP1 and IP1 to inositol)
-Glycogen synthase kinase-3 (inhibits neurotrophic and neuroprotective processes - so inhibiting it will increase neurotrophic effects)
Which molecules are important second messengers and are involved in manic episodes?
IP3 and DAG
-> causes α adrenergic and muscarinic transmission (may be hyperactive in mania)
Which enzyme produces IP3 and DAG?
Phospholipase C (PLC)
-cleaves the sugar-phosphate head off the inositol phospholipid -> generating IP3 and DAG
What are the effects of IP3 and DAG?
probably don’t need to know the details
IP3 binds channels on the endoplasmatic reticulum and causes Ca2+ release in the cell
-DAG stays in the plasma membrane and gets attached to the activated PKC -> newly released Ca2+ binds to PKC and starts a cascade that contributes to manic episodes
-blocking this pathway results in mood stabilization
KNOW That Lithium inhibits two enzymes in the recycling pathway that prevent the formation of IP3 and DAG
What effect does Lithium have on second messenger systems?
Side effects
it uncouples receptors from their G-proteins and thereby preventing second messenger action
-TSH binds to TSH-R on thyroid -> release of T3, T4
blocked by Lithium -> Hypothyroidism
-ADH (antidiuretic hormone): for water reabsorption -> blocked, so more urine output
-> nephrogenic Diabetes insipidus, Polydipsia, Polyuria
Others:
-Tremor
-Edema
-Ance
-Joint or muscle pain
-brittle nails/or hair
How is Lithium excreted?
entirely in the urine
-clearance is about 20% of creatinine
-Plasma half-life is about 20 hours
What are the signs of toxicity?
-vomiting, profuse diarrhea
-severe tremor, ataxia
-coma, and convulsions
can be caused by diuretics: sodium depletion can increase Lithium levels
-NSAIDs: decreases clearance
-Antipsychotics: more EPS
-narrow therapeutic index (2-3), monitor of Lithium levels needed
