Psychopharmacology Antipsychotic drugs

Dr. Layali Abbasi Psychiatrist

AL-Balqa Applied University

5th year/Faculty of Medicine 2019-2020

• Typical antipsychotics

• Atypical antipsychotics

Antipsychotic drugs

Antipsychotic drugs

• Conventional antipsychotics

Also called classical antipsychotics, or typical antipsychotics, or first-generation antipsychotics.

These drugs share the primary pharmacological property of D2 antagonism.

Typical antipsychotics

• Haloperidol

• Chlorpromazine

• Perphenazine

Haloperidol

• High potency FGA

• High risk of causing EPS

• Available as LAI

• D2 receptors in the mesolimbic dopamine system are postulated to mediate not only the positive symptoms of psychosis, but also the normal reward system of the brain, and the nucleus accumbens is widely considered to be the “pleasure center” of the brain. It may be the final common pathway of all reward and reinforcement, including not only normal reward (such as the pleasure of eating good food, orgasm, listening to music) but also the artificial reward of substance abuse.

• If D2 receptors are stimulated in some parts of the mesolimbic pathway, this can lead to the experience of pleasure.

• Thus, if D2 receptors in the mesolimbic system are blocked, this may not only reduce positive symptoms of schizophrenia, but also block reward mechanisms, leaving patients apathetic, anhedonic, lacking motivation, interest, and joy from social interactions, a state very similar to that of negative symptoms of schizophrenia.

• The near shutdown of the mesolimbic dopamine pathway necessary to improve the positive symptoms of psychosis may contribute to worsening of anhedonia, apathy, and negative symptoms, and this may be a partial explanation for the high incidence of smoking and drug abuse in schizophrenia.

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• Antipsychotics also block D2 receptors in the mesocortical DA pathway, where DA may already be deficient in schizophrenia.

• This can cause or worsen negative and cognitive symptoms even though there is only a low density of D2 receptors in the cortex.

• An adverse behavioral state can be produced by conventional antipsychotics, and is sometimes called the “neuroleptic induced deficit syndrome” because it looks so much like the negative symptoms produced by schizophrenia.

• When a substantial number of D2 receptors are blocked in the nigrostriatal DA pathway, this will produce various disorders of movement that can appear very much like those in Parkinson’s disease; this is why these movements are sometimes called drug-induced parkinsonism.

• Since the nigrostriatal pathway is part of the extrapyramidal nervous system, these motor side effects associated with blocking D2 receptors in this part of the brain are sometimes also called extrapyramidal symptoms, or EPS.

EPS -Acute dystonia

Intermittent and sustained contractions of muscles of tongue, face, neck and back.

Very frightening.

Typically occur during the first 5 days of treatment.

Mechanism: acute D2 antagonism.

Highest risk among young men treated with high potency agents.

Types of dystonia

• Oculogyric crisis (eyes rolled back in a locked position).

• Torticollis (spasm of cervical muscles of the neck).

• Laryngeal or pharyngeal dystonias.

• Macroglossia and tongue protrusion.

EPS -Acute akathisia Clinical features

-” Inability to sit still”, urge to move. - Subjective distress. - Akathisia can be confused with agitation. - Shifting the weight from foot to foot, walking on the

spot, inability to keep the legs still, feelings of inner restlessness.

- Onset: frequently after 5 days of treatment.

Akathisia- Management

• Reduce or change antipsychotic.

• Beta blockers (propranolol).

• High potency benzodiazepines (clonazepam).

EPS- Pseudoparkinsonism Clinical features

Masklike facies

Resting tremor

Bradykinesia

Cogwheel rigidity

Shuffling gait

Psychomotor retardation

Management of antipsychotic induced parkinsonism

• Dose reduction of antipsychotic agent.

• Anticholinergic agents:

Procyclidine

Biperiden

• Amantadine

EPS - Tardive dyskinesia

(TD)

• Hyperkinetic movement disorder that appears after prolonged use of dopamine antagonists (FGAs).

Tardive dyskinesia Clinical features

• Abnormal, repetitive, stereotyped, involuntary, painless, choreiform movement.

Ex: Sucking, smacking of lips

Tongue movements

Lateral jaw movements

Biological mechanism of Tardive dyskinesia

• Chronic blockade of D2 receptors in the nigrostriatal pathway induce up regulation of D2 receptors.

• Dopamine hypersensitivity.

Risk of TD

• Greater risk: elderly population, especially women (less likely to remit)

Pharmacological treatment of TD

• Most cases are not severe enough to warrant special treatment.

• There is no effective or standard treatment.

• Some strategies include:

- Taper antipsychotic.

- Switch antipsychotic.

- Drugs: clozapine.

Neuroleptic Malignant Syndrome

“ NMS is an acute disorder of thermoregulation and neuromotor control carrying a mortality

rate of about 21% when untreated”

NMS - Epidemiology

• Estimates of incidence were once around 3%

• Recent statistics suggest incidence of 0.01 -0.02%

• The syndrome has been described in all age groups (most are young adults)

NMS - Associated Drugs D

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Antipsychotics FGA

High potency

Low potency SGA

Antiemetics

NMS - Risk Factors

• Dehydration is present in about 92 % of patients ( risk factor or early complication?)

• Concomitant lithium use

• Use of high potency agents

• Long-acting injections

• High antipsychotic dose (not dose dependent)

NMS - Clinical Manifestations

Hyperthermia

• Higher than 38°C, even higher than 40°C

Rigidity

• Typical: “lead pipe rigidity”

Mental Status Changes

• Agitated delirium with confusion

Autonomic Instability

• Tachycardia, tachypnea, labile or high BP

NMS

Lab Testing

- Serum CK - Other abnormalities

- Leukocytosis - Electrolyte abnormalities

Management of NMS

• General

– Stop causative agent

– Supportive care

• Specific agents (limited evidence)

– Dantrolene

– Bromocriptine

– Amantadine

• ECT

• Dopamine D2 receptors in the tuberoinfundibular DA pathway are also blocked by conventional antipsychotics, and this causes plasma prolactin concentrations to rise, a condition called hyperprolactinemia.

• Hyperprolactinemia may cause: Galactorrhea (i.e., breast secretions) Amenorrhea (i.e., irregular or lack of menstrual periods). Interfere with fertility, especially in women. More rapid demineralization of bones, especially in

postmenopausal women who are not taking estrogen replacement therapy.

Sexual dysfunction and weight gain, although the role of prolactin in causing such problems is not clear.

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Muscarinic cholinergic blocking properties of conventional antipsychotics

• Differing degrees of muscarinic cholinergic blockade may also explain why some conventional antipsychotics have a lesser propensity to produce extrapyramidal side effects (EPS) than others.

• That is, those conventional antipsychotics that cause more EPS are the agents that have only weak anticholinergic properties, whereas those conventional antipsychotics that cause fewer EPS are the agents that have stronger anticholinergic properties.

Atypical antipsychotics

• Also called second-generation antipsychotics (SGAs).

• Serotonin–dopamine antagonists, with simultaneous serotonin 5HT2A receptor antagonism that accompanies D2 antagonism.

• Agonist actions at 5HT1A receptors and partial agonist actions at D2 receptors.

• All SGAs purportedly block 5-HT2A receptors. • SGAs provide greater blockade of 5-HT2A than D2

receptor blockade.

Atypical antipsychotics (SGAs)

• Risperidone

• Aripiprazole

• Amisulpride

• Quetiapine

• Ziprasidone

• Olanzapine

• Clozapine

Atypical antipsychotics (SGAs)

Although all atypical antipsychotics share a class warning for causing weight gain and risks for obesity, dyslipidemia, diabetes, accelerated cardiovascular disease, and even premature death, there is actually a spectrum of risk among the various agents.

High metabolic risk – clozapine, olanzapine

Moderate metabolic risk –risperidone,quetiapine

Low metabolic risk – aripiprazole, ziprasidone

Clozapine

• First of the SGAs

• Unique therapeutic benefits

• Unique side effects profile

Clozapine: Binding Profile

- D3 and D4 antagonist - 5HT1A partial agonist

Clozapine: Binding Profile

- High 5HT2A/D2 ratio - H1 antagonism - Muscarinic antagonism a 1 antagonism - 5HT2C antagonism

Clozapine: Clinical Profile

• Effective for treatment-resistant schizophrenia.

• Reduces violence and persistent aggression in schizophrenia.

• Long-term treatment associated with reduction of risk of suicidal behaviors.

Treatment-Resistant Schizophrenia

Treatment-Resistant

Schizophrenia

clozapine is the one and only clearly effective option

30%-45% of patients with schizophrenia

Clozapine: potential advantages and disadvantages

• Advantages

May benefit treatment-refractory patients

May reduce suicidal, aggressive, or violent behavior

May increase life expectancy

Has diminished extrapyramidal side effects

Minimizes risk for or improves tardive dyskinesia

Avoids hyperprolactinemia

Clozapine: potential advantages and

disadvantages

• Disadvantages Box warnings Agranulocytosis Seizures Myocarditis Orthostasis Increased mortality in dementia Other adverse effects Weight gain/metabolic syndrome Diabetic ketoacidosis Gastrointestinal hypomotility Sialorrhea

Clozapine – Adverse Effects Profile

• One of the antipsychotics with the lowest EPS risk

• One of the antipsychotics with the highest metabolic risk

• Risk of agranulocytosis

• Dose-dependent seizure risk

• Can be very sedating

Monitoring of clozapine-related agranulocytosis

• Monitor WBC, Differential

First 6 months: weekly monitoring (*)

6-12 months: every two weeks monitoring(*)

After 12 months: monthly monitoring(*)

(*) If WBC <= 3,500/mm3, ANC <= 2,000/mm3

Olanzapine: side effects

Severe weight gain and metabolic

effects Even one dose:

Insulin resistance

Endocrine/ inflammatory dysfunction

Risperidone: side effects

Hyperprolactinemia

Greater risk than other

SGAs

EPS

Greater risk than other

SGAs

Long-term effects

More easily managed

Not as serious as olanzapine

and quetiapine

Quetiapine – Clinical Profile

• Adverse effects:

– Most common adverse effects: somnolence and dizziness.

– Orthostatic hypotension

– Weight gain: intermediate risk

– EPS: low risk

Aripiprazole – Binding Profile

- Partial D2/D3 agonist (pre and postsynaptic receptors)

- 5HT2A antagonist - 5HT1A partial agonist - Modest affinity for H1,

M1 and a 1 receptors

Schizophrenia Psychopharmacology Algorithm

Duration: 4-6 week trial

Adequate trial

Lower than usual doses

First-episode: First antipsychotic trial

Start with SGA

• No difference with FGAs in acute efficacy

Long-term advantages

• Increased time to first relapse

• Better treatment retention

• Greater probability of staying in remission

FGAs

• Adjunctive anticholinergic use

• Adverse cognitive and central anticholinergic effects

THE END