Title: Anti-psychotics
1Anti-psychotics
- Mainstay of pharmacological treatment for
schizophrenia and related disorders - Diminish positive symptoms such as
hallucinations, delusions, thought disorder - Some impact on negative symptoms such as lack of
motivation, blunted affect, cognitive impairment - Important as a part of relapse prevention
2Anti-psychotics
- Antagonise dopamine receptors, resulting in
anti-psychotic effects - Indications-schizophrenia, acute mania, psychotic
depression, - Conventional and atypical
- Both of equivalent efficacy when taken at
recommended dosages - Atypicals have lower incidence of EPSE
3Dopamine Theory
- The dopamine hypothesis of psychosis
overactivity of dopamine neurons in the
mesolimbic pathway of the brain may mediate the
positive symptoms of psychosis - Mesolimbic pathway responsible for pleasure,
effects of drugs and alcohol and hallucinations
and delusions
4Blockade Of D2 Receptors?
5Dopamine Receptors
- Five subtypes D2 most important in terms of
psychosis - Blockade of mesolimbic receptors leads to reduced
psychotic symptoms - Blockade of the mesocortical pathway leads to
increased negative symptoms
6Dopamine Receptors
- Dopamine and acetylcholine have a reciprocal
relationship- - Blockade of dopamine receptors increases the
activity of acetylcholine - Over activity of acetylcholine causes EPSE
- Blockade of dopamine causes movement disorders in
the nigostriatal pathway - Long tem blockade causes upregulation and leads
to Tardive Dyskinesia
7Conventional or typical Antipsychotics
- Have four actions blockade of
- Dopamine 2
- Muscarinic/cholinergc
- Alpha adrenergic
- Histamine
8Serotonin and Dopamine Interactions
9The Dopamine Receptor Antagonist Hypothesis of
Antipsychotic drug Action
- Blockade of post synaptic dopamine receptors in
the mesolimbic pathway is thought to mediate the
efficacy of the drug and its ability to diminish
positive symptoms
10Receptor Affinity
- Low Affinity (loosely bound)
- - Quetiapine, Olanzapine, Amisulpride,
Clozapine - High Affinity (tightly bound)
- - Chlorpromazine, Haloperidol, Flupenthixol,
Fluphenazine - Tightly bound drugs lead to increased sensitivity
to dopamine blockade so more likely to cause EPSE
11Atypical Antipsychotics
- Pharmacologic Properties
- 5HT2A and D2 antagonism (as opposed to
conventional drugs which are D2 without 5HT2A
antagonism) - Atypicals blockade of D2 and 5HT2A
12Dopamine and Serotonin Receptors
- Dopamine and serotonin have a reciprocal
relationship - Serotonin opposes the release of dopamine in the
nigrostriatal and tuberofundibular pathways
13Dopamine and Serotonin Receptors
- Action of atypicals firstly binds to the D2
receptor - Secondly, binds to the 5HT2A receptor
- The second action reverses the first reverses
the blockade of D2 - Blocking 5HT2A disinhibits the dopamine neuron
causing dopamine to pour out
14Dopamine and Serotonin Receptors
- The dopamine and serotonin then compete with the
drug for the D2 receptor - Increased dopamine in the mesocortical pathway
- Reduction in movement disorders/EPSE for atypical
antipsychotics
15Atypicals
- In reality not simple serotonin-dopamine
antagonists - Most complex pharmacological properties
- Act on multiple serotonin and dopamine receptors,
histamine, alpha adrenergic cholinergic
16Atypicals versus conventional
- All equal efficacy (except Clozapine)
- Consideration for
- Merits of high versus low affinity drugs
- Cerebral selectivity of the drugs
- Adverse effect profile
- Dose necessary to achieve optimal D2 blockade
- Patient tolerability, preference, response
17Anti-psychotics
- Conventional eg chlorpromazine, haloperidol,
stelazine, depots such as flupenthixol,
zuclopenthixol, fluphenazine - Atypical eg olanzapine, risperidone,
quetiapine, amisulpride, clozapine, risperdal
consta intramuscular injection, aripiprazole,
paliperidone, ziprasidone - Also have effects on acetylcholine,
histamine,serotonin receptors varying adverse
effects
18Atypical antipsychotics
- The newer antipsychotics
- Effectively treat psychotic symptoms
- Lower incidence of extra pyramidal side effects
than conventional agents - Have effects on dopamine, serotonin, histamine
and muscarinic receptors
19Atypical antipsychotics
- Current atypicals in use in Australia are
- Amisulpride
- Aripiprazole
- Quetiapine
- Olanzapine
- Risperidone
- Clozapine
- Ziprasidone
- Paliperidone
20Therapeutic effects on symptoms
- Agitation, sleep and appetite often respond in
the first 1-2 weeks - Personal hygiene and basic interpersonal
socialisation may take 2-3 weeks and psychotic
symptoms can gradually decrease over 2-6 weeks - An effective trial should be at least 6-8 weeks
at doses that are within the prescribed range
21How long should antipsychotics be taken for?
- At least 6 months after an acute episode reduces
relapse rates - If the person experiences another episode they
may need antipsychotic medication for 2-5 years
before ceasing use - For those with multiple episodes, they may need
medication for much of their life
22Adverse Effects
- Sedation
- Postural hypotension
- Anticholinergic effects dry mouth, blurred
vision, constipation, urinary hesitancy - Weight gain-clozapine, olanzapine
- Metabolic effects-increased serum lipids,
impaired glucose tolerance-clozapine, olanzapine,
quetiapine
23Adverse Effects
- Hyperprolactinaemia-leads to
galactorrhoea, amenorrhoea, decreased libido - Sexual dysfunction
- QTc prolongation-leads to cardiac arrhythmias
- EPSE-extrapyramidal side effects
- Acute dystonias -laryngeal spasm, oculogyric
crises - Akathisia-severe sense of agitation, inner
restlessness in the limbs, especially the legs
24(No Transcript)
25Adverse Effects
- Akathesia a severe sense of psychomotor
agitation - Parkinsonism -poverty of movement, tremor,
rigidity, drooling, hypersalivation - Tardive dyskinesia-involuntary hyperkinetic
movements, affects the mouth, lips, tongue, jaws
with smacking, tongue writhing, sucking,chewing
and tic like movements,limbs and trunk can be
affected
26Adverse Effects
- Irreversible in some patients
- Neuroleptic malignant syndrome-rare but
potentially fatal high temp, muscle rigidity,
altered consciousness, raised creatinine kinase
cease medication - Can happen at anytime during treatment
- 30 patients will develop syndrome again on
rechallenge
27Depot Anti-psychotics
- Used when concerns around compliance
- Conventional-zuclopenthixol(useful for
agitated,aggressive,disturbed behaviour)
flupenthixol (may have mood elevating effects)
fluphenazine -EPSE common - Typical-Risperdal Consta onset of action 3
weeks, need oral Risperidone to supplement until
peak plasma reached
28Comparative Information for Anti-Psychotics
Chlorpromazine, Pericyazine Most sedating, most potent anticholinergic effects, least likely to cause EPSE, most likely to cause orthostatic hypotension. Low potency antipsychotics
Trifluperazine, Fluphenazine Moderately sedating, intermediate propensity to cause EPSE, some potential to cause orthostatic hypotension
Haloperidol, Droperidol, Thiothixene, Pimozide Least sedating, almost no anticholinergic effects, most likely to cause EPSE, least likely to cause orthostatic hypotension, sometimes referred to as high potency antipsychotics
29Atypical antipsychotics
Amisulpride Less potential for weight gain and sedation
Aripiprazole May cause insomnia, less potential for hyperprolactinaemia
Clozapine Effective treatment-resistant patients but has serious side-effects (blood dyscrasias, seizures, cardiomyopathy, myocarditis, orthostatic hypotension, sedation, weight gain).
30Atypical antipsychotics
Olanzapine Related to Clozapine may cause sedation, weight gain, peripheral oedema increased risk of stroke and related mortality in elderly dementia patients
Quetiapine Sedating and vasoactive, less potential for hyperprolactinaemia
Risperidone, Paliperidone Orthostatic hypotension and hyperprolactinaemia, may be a problem increased risk of stroke and related mortality in elderly dementia patients
Ziprasidone Less potential for weight gain
31Drug Interactions
- Cytochrome P450 isoenzymes are significant in
psychotropic drug interactions - Inducers or inhibitors of this pathway may
produce clinically important drug interactions - May lead to increase or decrease of medications
due to interactions
32Cytochrome P450
- Examples
- Fluvoxamine inhibits olanzapine and clozapine
metabolism - Smoking induces Olanzapine metabolism
- SSRIs inhibit most antipsychotics and therefore
increase serum concentrations - Phenytoin reduces serum concentration of
Quetiapine - Others grapefruit juice, Antibiotics,
33Clozapine
- Used when previously unresponsive to other
antipsychotics - Serious adverse effect profile
- Strict guidelines relating to commencement and
monitoring - Significant risk of agranulocytosis
- Trial at least 2 different standard
antipsychotics at an adequate dose and for an
adequate duration prior to commencing Clozapine
34Use of antipsychotics with older persons
- Various disorders treated with antipsychotics in
the elderly psychosis, bipolar affective
disorder, delirium dementia - Use extreme caution because of side effect
profile - Start low go slow (Malone et al 2007)
titrate over longer periods of time to reach the
required dose - Avoid polypharmacy wherever possible
35Pregnancy lactation
- Avoid antipsychotics if possible
- Use the lowest effective dose
- Neonatal adverse effects observed include
generalised hypertonicity and dystonic reactions
36Pregnancy lactation
- The safety of atypical agents is yet to be
established but preliminary reports there to be
no deleterious effects to the foetus - Isolated cases of congenital abnormalities with
the use of Clozapine
37Pregnancy Lactation
- No increased risk has emerged with the use of
Olanzapine - The conventional agents are generally preferred
- Supervised dose reduction and cessation 7-10 days
prior to delivery should be considered
38What other treatments are available?
- Remember that antidepressant medication is only
part of the - treatment for antenatal depression and anxiety.
Also consider - Psychological therapies
- Exclude organic illness as a cause of mental
health symptoms - Address any alcohol and/or illicit substance
abuse - Assess the social situation
- General lifestyle measures adequate rest/sleep,
balanced diet, exercise - The decision to treat should be made on an
individual case basis -
39Conclusion
- Conventional and atypical antipsychotics are used
as the foundation for pharmacological management
of schizophrenia and related psychosis - All have equal efficacy, exception Clozapine
- Atypicals generally better tolerated have less
EPSE - Atypicals first line treatment
- Start lowest effective possible dose titrate
upwards - Ongoing monitoring management of adverse
effects - Caution numerous drug interaction potential for
neuroleptic malignant syndrome
40Resources
- Therapeutic Guidelines Psychotropic Version 5
- www.tg.com.au 9329 1566
- Australian Medicines Handbook
- www.amh.net.au 08 8303 6977
- MIMS online
- http//www.ppmis.org.au Perinatal Psychotropic
Medicine Information Service