k26 - pharmacology of antipsychotic drugs
DESCRIPTION
Farmakologi FKTRANSCRIPT
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