Stahl Antipsychotics Chapter 5 - Passing Grades

Stahl Antipsychotics Chapter 5

Stahl Antipsychotics Chapter 5

28 April 2021

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extreme slowness or absence of motor movements as well behavioral indifferences p.131

D2 receptor antagonists

ability to block dopamine D2 receptors p.132

All of the conventional antipsychotic drugs (D2 antagonists) reduce

positive psychotic symptoms p.132

D2 receptor occupancy greater than

80% in the dorsal striatum is associated with extrapyramidal side effects, and in the pituitary with hyperprolactinemia p. 133

there is a narrow window between the threshold for

antipsychotic efficacy and that for side effects in terms of D2 binding p.133

Image: there is a narrow window between the threshold for

nucleus accumbens is widely considered to be the

pleasure center of the brain p.133

neuroleptic INDUCED Deficit syndrome

Deficit of dopamine within the mesocortical DA pathway as a result of D2 antagonism p.133

blockage of dopamine in the nigrostriatal dopamine pathway will

produce movement disorders, similar to Parkinson's disease and are called extrapyramidal symptoms (EPS) p.133

if chronic blockage of dopamine in the nigrostriatal dopamine pathway occurs, a hyperkinetic movement disorder known as

tardive dyskinesia occurs p.134

Approximately ________ of patients on conventional antipsychotics will develop tardive dyskinesia annually

5%, (25% every five years) p. 134

If resetting of D2 receptors does not occur or reset back to normal, the result is

tardive dyskinesia that is irreversible p. 135

risk of developing tardive dyskinesia in the elderly is as high as

25% within the first year of exposure to conventional antipsychotics p.134

patients who develop EPS early in treatment may be

twice as likely to develop tardive dyskinesia if treatment with conventional antipsychotic is continued chronically p.135

Neuroleptic Malignant Syndrome (NMS)

possibly related to D2 receptor blockade in the nigrostriatal pathway.
Rigidity, myoglobinuria, autonomic instability, hyperpyrexia, coma, death.
Treatment: dantrolene, D2 agonists (e.g., bromocriptine). p. 136

D2 blockage (antagonism) in the tuberoinfundibular pathway by conventional antipsychotics results in

increased plasma prolactin concentration, a condition called hyperprolactinemia, and is associated with galactorrhea and amenorrhea p. 136

Image: D2 blockage (antagonism) in the tuberoinfundibular pathway by conventional antipsychotics results in

hyperprolactinemia may lead to more

rapid demineralization of bones, especially in post-menopausal women not taking estrogen replacement p. 136

decrease dopamine in the mesolimbic dopamine to treat positive symptoms,
increase dopamine in the mesocortical dopamine to treat negative and cognitive symptoms, yet leave which pathways unchanged?

nigrostriatal and tuberoinfundibular dopamine pathway to avoid side effects p. 137

tuberoinfundibular D2 pathway projects from the

hypothalamus to the pituitary gland p. 137

many of the conventional antipsychotics share the ability to block

muscarinic cholinegic, histamine 1, and/or alpha1- adrenergic receptors p.137-138

Image: many of the conventional antipsychotics share the ability to block

type of symptoms with blockage of muscarinic-cholinergic receptors

dry mouth, constipation, blurred vision, drowsiness p.138

Image: type of symptoms with blockage of muscarinic-cholinergic receptors

type of symptoms with blockage of H1 receptors

weight gain, drowsiness p.139

type of symptoms with blockage of alpha 1-adrenergic receptors

orthostatic hypotension, drowsiness p. 140

conventional antipsychotics that have Weaker anticholinergic properties result in

more EPS symptoms p.138

conventional antipsychotics that have Stronger anticholinergic properties result in

less EPS symptoms p.138

dopamine normally inhibits acetylcholine release from

POSTsynaptic nigrostriatal cholinergic neurons, thus suppressing acetylcholine activity p. 139

if dopamine receptors are blocked by a conventional antipsychotic drug, what happens?

acetylcholine becomes overly active and is associated with EPS symptoms p. 139-140

Low potency conventional antipsychotics require

higher doses p.141

High potency conventional antipsychotics require

lower doses p.141

lower potency conventional antipsychotics have greater

anticholinergic, antihistaminic, and alpha 1 antagonist properties and probably more sedating in general p.141

what makes an antipsychotic Atypical?

D2 antagonism with 5HT2a antagonism

Image: what makes an antipsychotic Atypical?

Atypical antipsychotics have the CLINICAL profile of

equal positive symptom antipsychotic action, but low EPS symptosm, and less hyperprolactinemia compared to typical or conventional antipsychotics p. 141

As a Class, atypical antipsychotics are defined as

serotonin-dopamine antagonists (SDAs) p. 141

serotonergic neurons contain

MAO-B which has a low affinity for 5HT, so MOA-A degrades 5HT outside of the neuron p. 142

MAOA breaks down

serotonin and norepinephrine p. 142

MAOB breaks down

atypical antipsychotics

coupling of D2 antagonist and 5HT2A antagonism

Image: atypical antipsychotics

Serotonin synthesis

1. amino acid tryptophan is transported into the brain from the plasma as 5HT precursor
2. tryptophan hydroxylase (TRY-OH) converts tryptophan into 5-hydroxytryptophan (5HTP),
3. then aromatic amino acid decarboxylase (AAADC) converts 5HTP into 5HT
4. 5HTis then taken up in the synaptic vesicle via VMAT2, until release p. 142

Serotonin termination

1. terminated by MAO-A outside of the neuron once 5HT is released
2. SERT transports 5HT out of the synapse and back into the presynaptic nerve terminal p.142

all 5HT2A receptors are located

postsynaptic p. 142

5HT2A receptors located on cortical pyramidal neurons are

excitatory, and enhance downstream glutamate release p. 143

5HT2A stimulation (agonist) of cortical pyramidal neurons by serotonin hypothetically

Blocks dopamine release in the striatum via
1. stimulation of glutamate release in the brainstem that
2. triggers release of GABA p.143

Image: 5HT2A stimulation (agonist) of cortical pyramidal neurons by serotonin hypothetically

5HT2A blockage (antagonism) of cortical pyramidal neurons by Atypical antipsychotic interferes with serotonin, thus 5HT2A antagonism hypothetically

Stimulates dopamine release in the striatum
it does this by:
1. REDUCING glutamate release in the brainstem
2 FAILS to trigger release of GABA at dopamine neurons p. 143

5HT2A receptors theoretically regulate dopamine release from nigrostriatal dopamine neurons by

1. serotonin neurons whose cell bodies are in the midbrain raphe that innervate nigrostriatal dopamine neuros both at the level of the dopamine neuronal cell bodies in the substantia nigra
2. at the dopamine neuronal axon terminals in the striatum
3. This innervation may be either direct connection between the serotonin neuron and the dopamine dopamine neuron or
via an indirect connection with a GABA interneuronp. 143

blocking nigral and striatal 5HT2A receptors

increase dopamine release p. 148

Image: blocking nigral and striatal 5HT2A receptors

nigral and striatal 5HT2A receptors

decrease dopamine release p. 147

Image: nigral and striatal 5HT2A receptors

raphe 5HT1A receptors

increase dopamine release p.149

Image: raphe 5HT1A receptors

cortical 5HT1A receptors

increase dopamine release p. 146

Image: cortical 5HT1A receptors

normally serotonin inhibits

dopamine release, if no 5HT2A receptor is full on the DA neuron, dopamine is release, however if serotonin attaches to the 5HT2A receptor on the DA neuron, it stops the dopamine release p. 150

Atypical antipsychotics block (antagonism) D2 receptors at

60% versus the 80% which results in EPS symptoms p. 150

inhibits prolactin release p. 152

stimulates prolactic release p.152

5HT2A antagonism reverses the ability of

D2 antagonism to increase prolactin secretion p. 153

atypical antipsychotics almost always have a

higher affinity for 5HT2A receptors than D2 receptors

glutamate, glycine, GABA

amino acid neurotransmitters

The most common neurotransmitter in the brain. Excitatory. Involved with memory

An inhibitory neurotransmitter in the brain.

inhibitory neurotransmitter in the spinal cord

serotonin, histamine, dopamine, epinephrine, norepinephrine

monoamine transporters, also called biogenic amines

opioids = endorphins

dopamine, epinephrine, norepinephrine

risperdone, paliperidone, ziprasidone, iloperidone, lurasidone

clozapine, olanzapine, asenapine

aripiprazole, brexpiprazole

high metabolic risk

clozapine, olanzapine

moderate metabolic risk

risperidone, paliperidone, quetiapine, iloperidone (weight only)

low metabolic risk

ziprasidone, aripiprazole, lurasidone, iloperidone (low for dyslipidemia) asenapine, brexpiprazole?, cariprazine?

monitor four parameters to watch for cardiometabolic risk

1. BP,
2. weight,
3. fasting triglycerides,
4. fasting glucose,

2nd generation antipsychotics: Blood pressure and fasting glucose should be monitored at _______________, _________________, and _____________

baseline, 12 weeks, and annually

2nd generation antipsychotics: weight should be checked ________, and then at _____, ______, _______, and ___________thereafter

baseline, 4,8,12, and quarterly

2nd generation antipsychotics: waist circumference should be measured at _________ and __________

baseline and annually

2nd generation antipsychotics: fasting lipid monitoring should occur at _______, __________, and at _______________ providing the results are normal

baseline, 12 weeks, and 5 year intervals

FDA Black Box Warning on the use of antipsychotic medication in those with

Dementia, increased mortality in the elderly

9 or more medications or 12 or more doses per day

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