March 2015 Pharmacology of Antipsychotic drugs

Dr.Datten Bangun,MSc,SpFKDr.Sake J Martina SpFK

Dept.Farmakologi & TherapeutikFak.Kedokteran USU

Medan

Psychosis

• Definition: DSM IV = A severe mental disorder, with or without

organic damage, characterized by :• derangement of personality and• loss of contact with reality and • causing deterioration of normal social

functioning.

The hallmark of schizophrenia

Description: -Positive symptom: (known by their presence)

• delusions, hallucinations, abnormal movements, or thought disorders.

-Negative symptom: (characterized by absence)• social withdrawal, lack of affect, and reduced

motivation.- Cognitive symptoms (Disorganization of

thought and speech)

Negative Symptoms - A’sAffect Flattening

– Found in about 2/3 of schizophrenic patients– Often suggests a poor prognosis

Alogia – The failure to respond to questions or comments– Can also take the form of slow or delayed

responsesAvolition

– Inactivity or early loss of interest in ongoing activityAnhedonia

-inability to derive pleasure

Antipsychotics (Neuroleptics)

The Dopamine Hypothesis

1. Antipsychotic drugs block D2 dopamine receptors

2. Drugs that increase dopaminergic activity produce or exacerbate schizophrenia

3. Dopamine receptor density is increased in schizophrenia patients

4. PET shows increased D2 receptor density5. Successful treatment of schizophrenia changes

HVA in CSF of patients

Douglas L. Geenens, D.O. 2000

DA theory of schizophrenia

• DA is a transmitter in the mesocortical and mesolimbic pathways– Involved in cognition and emotion

• Increased activity of these pathways implicated in psychosis – Amphetamine releases DA and induces psychosis

• Blockade of the D2 dopamine receptor by all clinically effective antipsychotics– Correlates with antipsychotic potency

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Dopamine Pathways

Dopamine functions• Motor control - nigrostriatal system

– Deficiency results in rigidity, tremor and difficulty initiating movement

• Behavioural effects - mesolimbic system – Overactivity in rats leads to abnormal behavior

• Endocrine control - tubero-infundibular system– Dopamine and dopamine agonists suppress

prolactin release, dopamine antagonists may stimulate it

Dopamine PathwaysNigrostriatal

• Projects from the substania nigra to the basal ganglia-A part of the extrapyramidal system

• -Thus side effects are called “extrapyramidal”

• Controls movements

• The term “neuroleptics” refers to:

– Antipsychotics ability to “quiet the neurological system”

– To their neurological side effectsDouglas L. Geenens, D.O. 2000

Dopamine PathwaysNigrostriatal

• Types of movement disorders caused by this pathway include:– Akathisia- Dystonia- Tremor, rigidity, bradykinesia

• Drug-induced Parkinsonism• Chronic blockade can cause

Potentially irreversible movement disorder • “Tardive Dyskinesia”

Role is undeterminedDouglas L. Geenens, D.O. 2000

Dopamine PathwaysTuberoinfundibular

• Blockade produces galactorrhea • cause prolactin elevation

Douglas L. Geenens, D.O. 2000

Other transmitter systems involved..

+Why this notion? Because not every psychosis patients were succesfully treated by CPZ.

• Glutamatergic system dysfunction• e.g. effect of phencyclidine – blocker of NMDA

type of glutamate receptors• G-protein signaling abnormalities• Serotoninergic system abnormalities

• most antipsychotics also affect serotonin receptors

Dopamine and serotonin theory of schizophrenia NMDA indicates N-methyl-d-aspartate.)

Classification of antipsychotic drugs:

Typical Antipsychotic Drugs:

Phenothiazines:

Chlorpromazine,

Thioridazine ,

Trifluperazine,

Fluphenazine.

Butyrophenones:

Haloperidol

Benperidol.

Thioxanthenes:

Thiothixene

Others:

Pimozide

Loxapine

Atypical Antipsychotic Drugs:

Clozapine,

Olanzapine,

Risperidone,

Ziprasidone

Prof. Mohamed Adel

Classification of Antipsychotic drugs• Distinction between ‘typical’ and ‘atypical’

groups is not clearly defined, but rests on:1) Atypicals have less tendency to produce

motor side effects2)Atypicals produce effects on negative

symptoms of schizophrenia3)May have effects in therapy-resistant

patients

Mechanism of Action

• Most neuroleptics block central D2 receptors in the mesolimbic and mesocortical pathways.

• Newer drugs block both serotonergic and dopaminergic receptors.

PhenothiazinesTypical antipsychotic

Pharmacologic effects:

(1) Anti psychotic

(2) autonomic nervous system: block α-adrenergic and M-Cholinergic receptors and result in hypotension, dry mouth, constipation and blurred vision.

(3) Endocrine system: increase the release of prolactin and decrease corticotropin release and secretion of pituitary growth hormone.

Chlorpromazine

• Pharmacologic effects and mechanism:

(1)CNS: a. neuroleptic effect—

Antipsychotic drugs probably owe their therapeutic effects mainly to blockade of D2-receptors (lies in midbrain-cortex and midbrain-limbic system ).

•

•

D1, D5---D1-like receptors

D2-4------D2-like receptors

Chlorpromazine

• b. antiemetic effect--- inhibit chemoreceptor trigger zone or directly depress the medullary vomiting center.

• c. temperature-regulating effect--- produce hypothermia

Adverse Effects - EPS

Details on two main extrapyramidal disturbances (EPS):• Parkinson-like symptoms

– tremor, rigidity– direct consequence of block of nigrostriatal DA2 R

– reversible upon cessation of antipsychotics

• Tardive dyskinesia• involuntary movement of face and limbs• less likely with atypical antipsychotics (AP)• appears months or years after start of AP• ? result of proliferation of DA R in striatum

» presynaptic?• treatment is generally unsuccessful

Phenothiazines - Side effects

Weight gain – 40% - weight gain now attributed to ratio of binding to D2 and 5-HT2 receptors; possibly also histamine (for newer antipsychotics anyway)

Sexual dysfunction

• result from NE and SE blockade

• erectile dysfunction in 23-54% of men

• retrograde ejaculation

• loss of libido and anorgasmia in men and women

Seizures - <1% for generalized grand mal

Phenothiazines - Side effects

Neuroleptic malignant syndrome (NMS):

(1-2% early in trt)

• combination of motor rigidity, hyperthermia, and autonomic dysregulation of blood pressure and heart rate (both go up)

• can be fatal in 5-20% of cases if untreated

• treatment – discontinue meds; give trts for fever and cardiac problems

Treatment of NMS

• Discontinuation of dopamine antagonist• Monitoring vital signs, electrolytes, renal

output• Symptomatic treatment of fever • IV dantrolene/bromocriptine/amantadine• After symptoms subside – switch to atypical

anti-psychotic

Sensitivity to sun

• some phenothiazines collect in skin (chlorpromazine)

• sunlight causes pigmentation changes – grayish-purple splotching (look bruised)

• can also occur in eye and cause brown in cornea

• this produces a brownish cloud to vision and possibly permanent impairment

Agranulocytosis - <1%

• reduced white blood cell count

• lowered resistance to infection

• can be fatal

Jaundice – elevated bilirubin in liver - < ½%

Phenothiazines - Drug Interactions

• enzyme interactions with barbiturates (phenobarbital); phenytoin (Dilantin); carbamazepine (Tegretol) – reduce phenothiazine levels

• co-administration must be carefully monitored to prevent toxicity

• enzyme competition with SSRIs increases levels and may increase side effects

Autonomic side effects of antipsychotic drugs

• α1 AdrR blockade-orthostatic hypotension

• mAChR blockade – dry mouth, blurred vision, constipation, urinary retention

common with low potency drugs e.g. thioridazine, clozapine

Cardiac effects: QT, PR elongation, T wave changes, arrhythmias

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Other side-effects

• Ophtalmological effects: retinal pigmentation (thioridazine – irreversible, chlorpromazine – benign)

• Hepatological effects: obstructive jaundice• Neurologic : seizures

Haloperidole• entered US market in 1967

• more potent than phenothiazines, so doses are lower

• also have long half-life

• like phenothiazines, they block dopamine and norepinephrine receptors and show the related side effects

• extrapyramidal effects are worse (due to low blockade of ACh and thus worse ratio)

• but blood pressure effects are less

• reduced sedation

• no blood abnormalities or jaundice

REACTION FEATURES TIME OF MAXIMAL RISK

PROPOSED MECHANISM

TREATMENT 

Acute dystonia Spasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria

1 to 5 days Unknown Antiparkinsonian agents are diagnostic and curative

 

Akathisia Motor restlessness; not anxiety or "agitation"

5 to 60 days Unknown Reduce dose or change drug: antiparkinsonian agents,b benzodiazepines or propranololc may help

 

Parkinsonism Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait

5 to 30 days Antagonism of dopamine

Antiparkinsonian agents helpful  

Neuroleptic malignant syndrome

Catatonia, stupor, fever, unstable blood pressure, myoglobinemia; can be fatal

Weeks; can persist for days after stopping neuroleptic

Antagonism of dopamine may contribute

Stop neuroleptic immediately: dantrolene or bromocriptined may help: antiparkinsonian agents not effective

 

Perioral tremor ("rabbit" syndrome)

Perioral tremor (may be a late variant of parkinsonism)

After months or years of treatment

Unknown Antiparkinsonian agents often help

 

Tardive dyskinesia Oral-facial dyskinesia; widespread choreoathetosis or dystonia

After months or years of treatment (worse on withdrawal)

Excess function of dopamine hypothesized

Prevention crucial; treatment unsatisfactory  

a. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral antiparkinsonian agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle; with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).

Neurological Side Effects of antipsychotics

Extrapyramidal SymptomsDopamine Vs Acetylcholine

• Dopamine blockade: A relative increase in cholinergic activity

– causing EPS• Those antipsychotics that have significant

anti-ACH activity are therefore less likely to cause EPS

• When high potency antipsychotics are chosen, we often prescribe anti-ACH medication likeCogentin, diphenhydramine, or Artane

Douglas L. Geenens, D.O. 2000

H1 histamine receptor blockade effects

• Chlorpromazine was first found as an antihistamin• Sedation

• Increased appetite and weight gain

• Metabolic syndrome

Common with many atypical antipsychotics esp clozapine, olanzapine

Schizophrenia - Serotonin Hypothesis

correlation between DA affinity and antipsychotic efficacy has become weaker as a result of recently developed atypical antipsychotic medications that also show substantial affinity for 5HT2 receptors

Alteration of 5-HT transmission in the brains of schizophrenics patients have been reported in post-mortem studies and serotonin-agonists challenge studies

There are widespread and complex changes in the 5-HT system in schizophrenics patients

These changes suggest that 5-HT dysfunction is involved in the pathophysiology of the disease

Schizophrenia - Glutamate Hypothesis• Preclinical as well as clinical studies provide evidence of

hypofunction of NMDA receptors as a primary, or at least, a contributory process in the pathophysiology of schizophrenia

• Several clinical trials with agents that act at the glycine modulatory site on the NMDA receptor have revealed consistent reductions in negative symptoms and variable effects of cognitive and positive symptoms

• These studies also provide evidence that suggests the effects of clozapine on negative symptoms and cognition may be through activation of the glycine modulatory site on the NMDA receptor.

Antipsychotic Drugs – New Generations „atypical“

About 40-60% do not respond to phenothiazines or cannot handle side effects

• Questions remain about the efficacy of phenothiazines and haloperidole for negative symptoms

• Drugs needed that are low in extrapyramidal side effects and at least equal in efficacy for positive symptoms, perhaps better for negative

Antipsychotic Drugs – New Generations „atypical“

• clozapine• risperidone• olanzapine• sertindole• quetiapine etc.

Atypical antipsychotics

MARTA (multi acting receptor targeted agents)• clozapine, olanzapine, quetiapine

SDA (serotonin-dopamine antagonists)• risperidone, ziprasidone, sertindole

Selective D2/D3 antagonists• sulpiride, amisulpiride

Clozapine (1989)

• Selectively blocks dopamine D2 receptors, avoiding nigrostriatal pathway

• Also blocks NE

• More strongly blocks 5-HT2 receptors in cortex which then acts to modulate some dopamine activity

• Among non-responders to first generation meds or those who cannot tolerate side effects, about 30% do respond to Clozapine

Clozapine

• Extrapyramidal side effects are minimal

• May help treat tarditive dyskinesia

• Still shows orthostatic hypotension effects, sedation, weight gain, increased heart rate

• Increased risk for seizures (2-3%)

• Agranulocytosis in 1%

• Agranulocytosis risks increase when co-administered with carbamazepine

• Interactions with SSRIs and valproic acid increase Clozapine levels and risks

Risperidone (Risperdal; 1994)• Fewer side effects than Clozapine

• Marketed as first line approach to treatment

• Blocks selective D2, norepinephrine, and 5-HT2

• Argued as effective for positive and negative symptoms (controversial)

• Extrapyramidal side effects low (but are shown at high doses) - controversial

• Shares sedation, weight gain, rapid heart beat, orthostatic hypotension, and elevated prolactin

• No agranulocytosis risks

• May cause anxiety/agitation (possible OCD)

Risperidone (Risperdal)

• Research designs clearly stacked in favor of Risperidone re showing better profile for extrapyramidal side effects and for symptom reduction

• Advantages unclear other than agranulocytosis issue

Olanzipine - Zyprexa – 1996

• Same poorly supported arguments about improved negative symptom reduction

• Argued to be better than risperidone in extrapyramidal issues

• Does not cause prolactin elevation

• Same claim to fame reduced agranulocytosis risks

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Drug EPS WeightGain

MetabolicChangesb

↑ProlactinSecretion

↑QTInterval

Sedation Comments

Clozapine - +++ +++ - + +++ Can cause agranulocytosis, seizures, ↑salivation

Risperidone ++ ++ + +++ ++ +/-

Olanzapine + +++ +++ + + ++

Quetiapine + ++ + - ++ ++

Ziprasidone + - - - +++ + May improve cognitive function

Aripiprazole + - - - - +/- Partial agonist at D2

receptors and 5-HT1A

receptors

Table 2. Comparison of Atypical Antipsychotic Drugsa

a Important distinguishing features are highlighted.b ↑Risk for diabetes; worsening lipid profile.

Properties of conventional and atypical antipsychotic drugs

• All have equivalent clinical efficacy in treating positive symptoms

• None cause significant improvement in cognitive symptoms

• All take weeks to months to show effect

• Any single conventional will fail in about 30% of patients; these patients may respond to atypical drugs.

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Atypical antipsychotics advantages

• Maybe more effective against negative symptoms

• Less likely to cause EPS and TDs

• More favorable side effect profile improves compliance

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Metabolic syndrome and atypical antipsychotic drugs

• Increased risk of diabetes

• Worsening lipid profile

• No clear association with weight gain; mechanism unknown

• Caution and frequent monitoring in patients with family history of diabetes or cardiovascular disease

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Treatment of medication-induced movement disorders

• Parkinsonism– anticholinergics, amantadine

• Acute dystonia – anticholinergics (IM)

• Akathisia – beta-blockers, BZ

• Tardive dyskinesia – clozapine

Long acting anti-psychotics• Indicated mainly for patients with low compliance

to treatment• IM:

• Haloperidol - Halidol decanoas • Fluphenazine – Modiket• Zuclopenthixol – Clopixol depot• Flupenthixol – Fluanxol depot• Risperidone – Risperidal consta

• PO:• Penfluridol – Semap

Clinical Uses

Treatment of schizophrenia. • The typical neuroleptics ameliorate

positive symptoms of schizophrenia.

• The atypical neuroleptics (Clozapine & Risperidone) ameliorate mainly the negative symptoms.

Clinical Uses (cont’d)• Antipruritic: promethazine used as antipruritic

due to H1- receptor blockade.• Chronic pain with severe anxiety (neuroleptic

+ opioid drug).• Tranquilizer in management of agitated and

disruptive behavior.• Preanesthetic medication (promethazine) to

produce sedation.• Intractable hiccups (chlorpromazine)

Clinical Uses (cont’d)

• Antiemetic (prochlorperazine) is used to stop all types of vomiting: Except in cases of:

-Motion sickness (treated by blocking M-receptors in vomiting center by hyoscine)

-Vomiting associated with Parkinsonism (neuroleptics block D-receptors aggravate Parkinsonism).

Fig 1. Yearly change in the number of hospitalized patients with psychiatric disorders (thousands).

Hospital beds occupied by patients with psychiatric disorders

Thank you for the attention