neuroleptic

Neurolepticsprof Dr Elham Aljammas2016

Antipsychotics used to treat schizophrenia.
Schizophrenia is a severe chronic disorder
Positive symptoms: hallucinations, and delusions
Negative symptoms: amotivation, poverty of speech, flat affect
Disorganized symptoms: speech, thought, and behavior
Now being used to treat Bipolar as well

Antipsychotics

Indications for use:
schizophrenia, schizoaffective disorder, bipoalar disorder- for mood stabilization and/or when psychotic features are present, delirium,
psychotic depression,
dementia,
trichotillomania, augmenting agent in treatment resistant anxiety disorders.

Pathways affected by DA in the Brain

Antagonize dopamine – block a specific receptor

Atypical
Risperdal - Risperidone
Olanzepine - Zyprexia
Quetiapine - Seroquel
Ziprasidone – Geodon
Aripiprazole – Abilify
Paliperidone – Invega

Typical

Chlorpromazine
Trifluperazine Thorazine
Haloperidol – (Haldol)

The Atypical Antipsychotics

- atypical agents are serotonin-dopamine 2 antagonists (SDAs)
They are considered atypical in the way they affect dopamine and serotonin neurotransmission in the four key dopamine pathways in the brain.

Antipsychotics drugs(typical)

Usual dose
drug
group
100-1500mg daily
chlorpromazine
phenothiazines
5-30mg daily
50-100mg IMI monthly
5mg IMI orIVI on need
haloperidol
butyrophenones
40-200mg fortnight
Short & long acting
flupentixol
thioxanthenes
4-30mg daily
1,5,10mg orally
Pimozide
stelazine
Diphenylbutylpiperidines
Trifluperazine
600-1800mg daily
25 mg IMI monthly
Sulpiride
Modecate
Substituated benzamides
Fluphenazine decanoate


Neuroleptics
. The traditional or typicalneuroleptic drugs (also called conventional or first-generation antipsychotics) are competitive inhibitors at a variety of receptors, but their antipsychotic effects reflect competitive blocking of dopamine receptors. These drugs vary in potency. For example, chlorpromazine is a low-potency drug, and fluphenazine is a high-potency agent No one drug is clinically more effective than another.

Atypical antipsychotic agent

Usual dose
drugs
group
25-900mg daily
clozapine
dibenzodiazepine
2-16mg daily
100-200mg/d

Risperidone

Seroquel

Bezisoxazole

Quetiapine -

5-20mg daily

olanzapine
thienobenzodiazepine


Atypical
atypical agents are serotonin-dopamine 2 antagonists (SDAs)
They are considered atypical in the way they affect dopamine and serotonin neurotransmission in the four key dopamine pathways in the brain.

Mechanism of action

Dopamine receptor blocking activity in the brain:. D1 and D5 receptors activate adenylyl cyclase, often exciting neurons, whereas D2, D3 and D4 receptors inhibit adenylyl cyclase, or mediate membrane K+ channel opening leading to neuronal hyperpolarization. The neuroleptic drugs bind to these receptors to varying degrees. However, the clinical efficacy of the typical neuroleptic drugs correlates closely with their relative ability to block D2 receptors in the mesolimbic system of the brain. atypical drug clozapine has higher affinity for the D4 receptor and lower affinity for the D2 receptor, which may partially explain its minimal ability to cause extrapyramidal side effects (EPS).

Serotonin receptor blocking activity in the brain: Most of the newer atypical agents appear to exert part of their unique action through inhibition of serotonin receptors (5-HT), particularly 5-HT2A receptors. (clozapine ,olanzapine,aripiprazole , Quetiapine ).

The undesirable side effects of these agents, however, are often a result of actions at these other receptors.
Antipsychotic actions: All of the neuroleptic drugs can reduce the hallucinations and delusions associated with schizophrenia by blocking dopamine receptors in the mesolimbic system of the brain. The antipsychotic effects usually take several days to weeks to occur, suggesting that the therapeutic effects are related to secondary changes in the corticostriatal pathways.

Extrapyramidal effects: Dystonias (sustained contraction of muscles leading to twisting distorted postures), parkinson-like symptoms, akathisia (motor restlessness), and tardive dyskinesia (involuntary movements of the tongue, lips, neck, trunk, and limbs) occur with chronic treatment. Blocking of dopamine receptors in the nigrostriatal pathway probably causes these unwanted movement symptoms. The atypical neuroleptics exhibit a lower incidence of these symptoms.

Antiemetic effects: With the exceptions of aripiprazole and thioridazine , most of the neuroleptic drugs have antiemetic effects that are mediated by blocking D2-dopaminergic receptors of the chemoreceptor trigger zone of the medulla.
Antimuscarinic effects: Some of the neuroleptics, particularly thioridazine, chlorpromazine, clozapine, and olanzapine ,produce anticholinergic effects, including blurred vision dry mouth (exception: clozapine increase salivation), confusion, and inhibition of gastrointestinal and urinary tract smooth muscle, leading to constipation and urinary retention. This anticholinergic property may actually assist in reducing the risk of EPS with these agents.

Important side effects to be considered when choosing antipsychotic drugs

1-Extrapyramidial side effects:
Atypical antipsychotic has less extrapyramidal effect.











2-hyperprolactinaemia: Lead to menstrual disturbances,increased risk of malignancy,increased galactorrhea,& increased osteoporosis.
Prolactine sparingis aripiprazole
3-sedationIncreased sedation with high affinity to histamine& muscarinic receptors
• CPZ,olanzapine,clozapine
Helpful in acute state

4-weight gain:

Histamine & 5HT R block
(>olanzapine)less with resperidone,amisulpride,&aripipraz 5.Type 11 DM
>clozapine &olanzapine
Should be monitored by Bd sugar,lipid profile& weight.

6-CV& cerbrovascular events ,

through their effect on the
lipid profile ,Wt,& insulin
resistance. Some produce prolonge QT interval.
olanzapine& resperidone
7-postural hypotension

8-sexual dysfunction

9-photosensitivity

10-agranulocytosis

11-constipation

12-reduction of fit threshold

Other effects: Blockade of -adrenergic receptors causes orthostatic hypotension and light-headedness. The neuroleptics also alter temperature-regulating mechanisms and can produce poikilothermia (body temperature varies with the environment). In the pituitary, neuroleptics block D2 receptors, leading to an increase in prolactin release. Atypical neuroleptics are less likely to produce prolactin elevations. Sedation occurs with those drugs that are potent antagonists of the H1-histamine receptor, including chlorpromazine, olanzapine, quetiapine, and clozapine. Sexual dysfunction may also occur with the antipsychotics due to various receptor-binding characteristics.

Therapeutic uses

Treatment of schizophrenia:
The neuroleptics are considered to be the only efficacious treatment for schizophrenia.
Prevention of severe nausea and vomiting: The older neuroleptics (most commonly prochlorperazine) are useful in the treatment of drug-induced nausea

Other uses: The neuroleptic drugs can be used as tranquilizers to manage agitated and disruptive behavior secondary to other disorders.
Neuroleptics are used in combination with narcotic analgesics for treatment of chronic pain with severe anxiety
. Chlorpromazine is used to treat intractable hiccups.
Promethazine, this agent is used in treating pruritus .


Pimozide is primarily indicated for treatment of the motor and phonic tics of Tourette's disorder. risperidone and haloperidol are also commonly prescribed for this tic disorder.
Also, risperidone is now approved for the management of disruptive behavior and irritability secondary to autism

Antipsychotic adverse effect

Tardive Dyskinesia (TD)-involuntary muscle movements that may not resolve with drug discontinuation- risk approx. 5% per year
Neuroleptic Malignant Syndrome (NMS): Characterized by severe muscle rigidity, fever, altered mental status, autonomic instability, elevated WBC, CPK and lfts. Potentially fatal.
Extrapyramidal side effects (EPS): Acute dystonia, Parkinson syndrome, Akathisia

Adverse effects

. Parkinson-like symptoms of bradykinesia, rigidity, and tremor usually occur within weeks to months of initiating treatment. Clozapine can produce bone marrow suppression, seizures, and cardiovascular side effects. The risk of severe agranulocytosis necessitates frequent monitoring of white-blood-cell counts

. The neuroleptics depress the hypothalamus, affecting thermoregulation, and causing amenorrhea, galactorrhea, gynecomastia, infertility, and impotence. Significant weight gain is often a reason for noncompliance. It is also recommended that glucose and lipid profiles be monitored in patients taking antipsychotics

The choice of medication &dose :depend on

1-sevirety of the problems.
2-degree of sedation required.
3-side effect profile.
4-preferance of individual clinician.

Study Questions

Choose the ONE best answer.
13.1 An adolescent male is newly diagnosed with schizophrenia. Which of the following neuroleptic agents may improve his apathy and blunted affect?
A. Chlorpromazine.
B. Fluphenazine.
C. Haloperidol.
D. Risperidone.
E. Thioridazine


Correct answer = D. Risperidone is the only neuroleptic on the list that has some benefit in improving the negative symptoms of schizophrenia. All the agents have the potential to diminish the hallucinations and delusional thought processes.

Which one of the following neuroleptics has been shown to be a partial agonist at the D2 receptor?
A. Aripiprazole.
B. Clozapine.
C. Haloperidol.
D. Risperidone.
E. Thioridazine.

Correct answer = A. Aripiprazole is the agent that acts as a partial agonist at D2 receptors. Theoretically, the drug would enhance action at these receptors when there is a low concentration of dopamine and would block the actions of high concentrations of dopamine. All the other drugs are only antagonistic at D2 receptors, with haloperidol being particularly potent.

A 21-year-old male has recently begun pimozide therapy for Tourette's disorder. He is brought to the emergency department by his parents. They describe that he has been having “different-appearing tics” than before, such as prolonged contraction of the facial muscles. While being examined, he experiences opisthotonus (spasm of the body where the head and heels are bent backward and the body is bowed forward. A type of extrapyramidal effect). Which of the following drugs would be beneficial in reducing these symptoms?
A. Benztropine.
B. Bromocriptine.
C. Lithium.
D. Prochlorperazine.
E. Risperidone

Correct answer = A. The patient is experiencing extrapyramidal symptoms due to pimozide, and a muscarinic antagonist such as benztropine would be effective in reducing the symptoms. The other drugs would have no effect or, in the case of prochlorperazine, might increase the symptoms.

A 28-year-old woman with schizoid affective disorder and difficulty sleeping would be most benefited by which of the following drugs?
A. Aripiprazole.
B. Chlorpromazine.
C. Haloperidol.
D. Risperidone.
E. Ziprasidone.


Correct answer = B. Chlorpromazine has significant sedative activity as well as antipsychotic properties. Of the choices, it is the drug most likely to alleviate this patient's major complaints, including her insomnia

Prof. Dr Elham Aljammas

Anxiolytic

Anxiolytic

Treat anxiety disorders
Generalized Anxiety Disorder
Panic Disorder
PTSD
OCD
Social Anxiety Disorder (SAD)

Anxiolytic

Used to treat many diagnoses including panic disorder,
generalized Anxiety disorder,
substance-related disorders and their withdrawal,
insomnias and parasomnias.
In anxiety disorders often use anxiolytics in combination with SSRIS or SNRIs for treatment.


Benzodiazepines
Used to treat insomnia, parasomnias and anxiety disorders.
Often used for CNS depressant withdrawal protocols ex. ETOH withdrawal.
Side effects/cons
Somnolence
Cognitive deficits
Amnesia
Disinhibition
Tolerance
Dependence

• Drug

• Dose Equivalency (mg)
• Peak BloodLevel (hours)
• Elimination Half-Life1 (hours)
• Comments
• Alprazolam (Xanax)
• 0.5
• 1-2
• 12-15
• Rapid oral absorption
• Chlordiazepoxide (Librium)
• 10.0
• 2-4
• 15-40
• Active metabolites; erratic bioavailability from IM injection
• Clonazepam (Klonopin)
• 0.25
• 1-4
• 18-50
• Can have layering effect
• Diazepam (Valium)
• 5.0
• 1-2
• 20-80
• Active metabolites; erratic bioavailability from IM injection
• Flurazepam (Dalmane)
• 30.0
• 1-2
• 40-100
• Active metabolites with long half-lives
• Lorazepam (Ativan)
• 1.0
• 1-6
• 10-20
• No active metabolites
• Oxazepam (Serax)
• 15.0
• 2-4
• 10-20
• No active metabolites
• Temazepam (Restoril)
• 30.0
• 2-3
• 10-40
• Slow oral absorption
• Triazolam (Halcion)
• 0.25
• 1
• 2-3
• Rapid onset; short duration of action

Monitor for efficacy and tolerance and adjust as indicated.

If the patient does not improve step back, rethink your diagnosis and treatment plan!
Keep an eye on drug-drug interactions

Benzodiazepines

Facilitate GABA neurotransmission
Bind to a particular site on the GABA receptor
Xanax, Ativan, Valium, Serax, Librium
Beta-Blockers
Antagonize NE by blocking Beta receptor subtype
SSRIs
PTSD, OCD, SAD, and to some degree GAD
Others
Buspar
Non-sedating
Does not interact with alcohol
Not highly effective


ADD
Methylphenidate – Ritalin
DA reuptake inhibitor
So slowly it enters the brain that it is not addictive like cocaine even though they have the same mechanism
Concerta (Immediate release combined with time release)
Adderal (mixed amphetamine salts)
Has extended release
Modafinil – Provigil
Vyvanse
An amphetamine pro-drug
Less abusable
Straterra

Mixing Med.

Although classified as a certain type of drug most psych meds used for many different disorders.
Antipsychotics in Bipolar Disorder
Abilify
Zyprexa
Mood stabilizers in alcoholism
Topiramate
Prescribing a medication for a disorder when it is known to work, but there is no formal FDA indication is called “off-label prescribing”
It’s perfectly legal and quite common


Thank You