Psychopharmacology Exam 2 (part 3)

46問 • 10ヶ月前

問題一覧

"Go Pathway"...populated with D1 receptors (excitatory), projects directly from striatum to globus pallidus interna, stimulates movement

Direct pathway

"Stop Pathway"..populated with D2 receptors (inhibitory), projects indirectly to globus pallius interna via globus pallidus externa and subthalamic nuclei, normally blocks movement, dopamine inhibits its action D2 receptors

Indirect pathway

Too little dopamine here causes movement disorders like Parkinson’s disease, akathisia, and dystonia

Nigrostriatal Pathway

Too much dopamine here causes hyperkinetic movement disorders like chorea, dyskinesias, and tics.

Nigrostriatal Pathway

What is the mechanism that can lead to tardive dyskinesia?

Blockade of D2 receptors in the Nigrostriatal Pathway

• GABA neurons projecting from striatum to globus pallidus interna is activated • GABA neuron projecting from striatum to globus pallidus externa is activated • GABA release inhibits activity of another GABA neuron projecting to thalamus • GABA release inhibits activity of another GABA neuron projecting to subthalamic nucleus (STN) • Without GABA release in thalamus, glutamate neuron is activated • Without GABA release in STN, glutamate neuron is activated • Glutamate is released into the cortex • Movement is stimulated

Direct Pathway Activation of the Nigrostriatal Pathway

• GABA neuron projecting from striatum to globus pallidus externa is activated • GABA release inhibits activity of another GABA neuron projecting to thalamus • GABA release inhibits activity of another GABA neuron projecting to subthalamic nucleus (STN) • Without GABA release in thalamus, glutamate neuron is activated • Without GABA release in STN, glutamate neuron is activated • Glutamate is released into the cortex • Movement is stimulated • Glutamate is released into globus pallidus interna -> stimulates GABA neuron to release GABA in thalamus • GABA binds to glutamate neuron and inhibits glutamate release into cortex • Movement is inhibited

Indirect Pathway Activation in the Nigrostriatal Pathway

Onset: 4 hours Features: Facial grimacing, involuntary upward eye movement, muscle spasms of the tongue, face, neck and back (back muscle spasms cause trunk to arch forward), laryngeal spasms

Acute dystonia

Onset: 4 weeks Features: Restless, trouble standing still, paces the floor, feet in constant motion, rocking back and forth

Akathisia

Onset: 4 days Features: Stopped posture, shuffling gait, rigidity, bradykinesia, tremors at rest, pill-rolling motion of the hand

Akinesia (Parkinsonian symptoms)

Onset: 4 months Features: Protrusion and rolling of the tongue, sucking and smacking movements of the lips, chewing motion, facial dyskinesia, involuntary movements of the body and extremities

Tardive dyskinesia

Spasm of the extra orbital muscles, causing upwards and outwards deviation of the eyes

Oculogyric crisis

Sustained, forced, involuntary closing of the eyelids

Blephorospasm

Head held turned to one side

Torticollis

Painful forced extension of the neck. When severe the back is involved and the patient arches off the bed.

Opisthotonus

The tongue does not swell, but it protrudes and feels swollen

Macroglossia

May be accompanied by trismus (inability to normally open the mouth), risus sardonicus (highly characteristic, abnormal, sustained, spasm of the facial muscles that appears to produce grinning), dysarthria and grimacing.

Buccolingual crisis

Trunk muscles and less commonly limbs can be affected in acute dystonia

Spasticity

Abnormal and prolonged contraction of the muscles of the eyes, head, neck, limbs, or trunk developing within a few days of starting or raising the dosage of a medication or after reducing the dosage of a medication used to treat extrapyramidal symptoms.

Medication-Induced Acute Dystonia

Discuss the mechanism behind DIP.

D2 normally suppresses ACh. When a D2 antagonist are introduced this leads to a downstream effect that effectively causes enhances ACh release which causes DIP.

Discuss the mechanism that restores the normal balance between dopamine and acetyocholine that can reverse the symptoms of DIP, and name the drugs involved.

Anti-cholinergics (Diphenhydramine and Benztropine) block muscarinic cholinergic receptors (M1 receptors)

Blocking of these receptors can reduce DIP but can also induce S/E such as constipation, blurred vision, dry mouth, drowsiness, and cognitive dysfunction. As a result, can lead to a paralytic ileus!

M1 receptors

Subjective complaints of inner restlessness and very easy to miss and mistake for anxiety, often accompanied by observed excessive movments (eg fidgety movements of the legs, rocking from foot to foot, pacing, inability to sit or stand still), developing within a few weeks of starting or raising the dosage of a medication (eg neuroleptic) or after reducing the dosage of a medication used to treat EPS.

Akathisia

What is the screening tool used for Akathisia, and treatment options?

Barnes Akathisia Scale; Beta Blockers (1st line), Benzodiazepines (2nd line), then Amantadine, Cogentin, 5HT2A Antagonists (Trazodone, Remeron), Cyproheptadine, Vit B6 600 mg BID (for subjective symptoms only)

Discuss the subjective and objective symptoms of Akathisia

Subjective: inner restlessness Objective: restless movements (pacing)

What is the major advantage that atypicals have over typicals with regards to S/E?

Atypicals have 1/2 the rate of TD

Discuss the difference between Neuroleptic Withdrawl-Emergent Dyskinesia vs. Tardive Dyskinesia

Symptoms may develop after a shorter period of medication use in eldery patients. In some patients, movements of this type may appear after discontinuation, or after change or reduction in dosage, of neuroleptic medications, in which cases the condition is called Neuroleptic Withdrawl-Emergent Dyskinesia. Because withdrawal-emergent dyskinesia is usually time-limited, lasting less than 4-8 weeks, dyskinesia that persists beyond this window is considered to be Tardive Dyskinesia.

What is the mechanism that causes Tardive Dyskinesia?

Chronic blockage of D2 receptors in the nigrostriatal pathway causing an upregulation of D2 receptors

Nigrostriatal D2 receptors that are sensitive to D2 blockade may trigger a form of neuroplasticity called “supersensitivity” in reaction to chronic blockade.

Levodopa-Induced Tardive Dyskinesia

Discuss how the "Stop Pathway" normally works, how it works in DIP and how that differs in how it works in TD.

Dopamine inhibits the "Stop Pathway" which makes you "Go" and allows for normal movement. D2 antagonists blocks dopamine from inhibiting the "Stop Pathway" which makes you "Stop" causing DIP. This chronic blocking of D2 receptors by D2 antagonists cause major inhibition ("Go..Go...Go") of the "Stop Pathway" causing upregulated supersensitive D2 receptors

What is the only treatment for TD and how does it work?

VMAT2 inhibitor; inhibition of VMAT2 prevents dopamine from being taken up into synaptic vesicles leading to dopamine depletion and reduction in symptoms of TD

FDA approved to treat Huntington's Chorea (not TD), is a prodrug, short 1/2 life (requires TID dosing), substrate for CYP 2D6 into 4 active metabolites of which +beta/VMAT2 has the most therapeutic effects, risk for depression and suicide, very sedating, and can cause DIP.

Tetrabenazine (Xenazine)

FDA approved to treat Huntington's Chorea and TD, less favorable substrate for CYP 2D6 due to "heavy hydrogen" of which Deu + Beta/VMAT2 is the active metabolite that has the most therapeutic effects, allows for a longer 1/2 life, BID dosing with food (no calories specified), and no suicide warning

Deutetrabenazine (Austedo)

FDA indicated to teat TD ONLY, the slow hydrolysis of the active metabolite +alpha dihydro tetrabenazine allows for once daily dosing, long 1/2 life, and no need for food, no suicide warning, and is not a substrate for CYP 2D6.

Valbenazine (Ingressa)

Whats the major differences between the mechanisms of the "Go" and "Stop" pathways?

The "Go" or direct pathway is activated by dopamine via D1 receptors, and the "Stop" or indirect pathway is activated by dopamine in the D2 receptors. Both lead to a downstream effect of enhancing motor output.

How much VMAT2 inhibition is needed for adequate efficiacy in TD treatment?

90%

What is the major difference in how the mechanism of VMAT2 inhibition works in the Direct vs Indirect Pathways?

VMAT2 inhibition works in both but the major difference is the receptor binding; the Direct Pathway involves D1 receptors whereas the Indirect Pathway involves D2 receptors. Depletion of dopamine via VMAT2 through these two pathways leads to stopping of TD movements.

Dopamine’s action here normally inhibits the release of prolactin. When dopamine is blocked in this pathway, prolactin levels rise

Tuberoinfundibular Pathway

Symptoms of hyperprolactinemia include:

-Gynecomastia (breast enlargement or breast development) -Galactorrhea (breast secretions) -Amenorrhea (loss of menstrual periods) -Oligomenorrhea (irregular/disrupted menstrual periods) -Sexual dysfunction (hypogonadism, infertility) -Osteoporosis

Discuss the normal range for prolactin in general and in specific populations, and what level is considered very high.

Normal prolactin range: 5 - 20 ng/ml Males: < 20 ng/ml Non-pregnant females: 5 - 40 ng/ml Pregnant women: 80 - 400 ng/ml Very high levels: > 200 ng/ml

Discuss differential diagnoses for possible causes of hyperprolactinemia

Pregnancy, Stress, Exercise, High-Protein Meals, Tumors, Drugs (antipsychotics, metoclopramide (reglan), methyldopa), Estrogen, Hypothyroidism, Chronic Renal Failure

What are the recommendations from the Endocrine Society regarding checking prolactin levels?

It’s recommended that you not routinely check prolactin levels in an otherwise asymptomatic patient

What instructions should you give patients prior to checking a prolactin level?

We will check it in the morning (few hours after waking), and that they should be fasting and avoid stress or strenous exercise 20 - 30 mins prior to lab draw

Although there is no authoritative recommendation as to when hyperprolactinemia requires intervention, discuss management strategies for antipsychotic-induces hyperprolactinemia

1) Switch Antipsychotic to a prolactin-sparing one (aripiprazole, brexpiprazole, cariprazole, or clozapine) 2) Add Aripiprazole 3) Add a Dopamine Agonist (bromocriptine and cabergoline)

What is the herbal option for treating hyperprolactinemia?

Peony-glycyrrhiza decoction 45 g/day

What is the risk of treating hyperprolactinemia with a dopamine agonist such as bromocriptine or cabergoline?

Increases the risk of Psychosis

Patho Renal

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