psychopharmacs : antipsychotics prof. mudr. eva Češková, csc. dept. of psychiatry, dept. of...
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Psychopharmacs : antipsychotics
prof. MUDr. Eva Češková, CSc.prof. MUDr. Eva Češková, CSc.
Dept. of Psychiatry, Dept. of Psychiatry,
Masaryk University , BrnoMasaryk University , Brno
Psychopharmacs : antipsychotics
definition and historyclassification according to chemistry classification according to clinical efficacymechanism of actionpharmacokineticdoses and duration of treatment side effects indication literature
Definition, history
Neuroleptics ( antipsychotics, AP ) are
psychopharmacs influencing psychic integration
in a positive way
Antipsychotics are the cornerstone of treatment
of schizophrenia.
The first antipsychotic drugs was discovered by
accident in the 1950s when a drug thought to be
an antihistamine (chlorpromazine) was
serendipitously observe to have unique
antipsychotic effect
Classification according to chemistryphenothiazines - 3 ring nucleus, drugs differ in the side
chains(aliphatics, piperidines, piperazines) thioxanthenes - differ from the phenothiazine by the
substitution of a C instead of N in the middle ringbutyrophenones (haloperidol)dephenylbutyrylpiperidines (penfluridol, pimozid)dibenzodiazepines (clozapine)benzisoxale (risperidone) thienobenzodiazepine (olanzapine)dibenzothiazepine (quetipine)benzamide others
Classification according to the clinical efficacy
Conventional antipsychotics: incizive (high potency):e.g., haloperidol,
fluphenazine, perphenazine, trifluoperazine) basale (low potency):e.g., chlorpromazine ,
thioridazine
Atypical antipsychotics:
aripiprazole, clozapine, olanzapine,
risperidone , quetiapine , ziprasidone, zotepine
Conventional antipsychotics
Limitations of conventional antipsychotics: insufficient efficacy with targeted symptoms
(e.g., negative symptoms, cognitive deficits) positive symptoms resistant to therapy in (15–
48% of patients)motor side effects (irreversible tardive dyskinesia
in 5–10% of patients with long-term treatmentaffective side effects (dysphoria, anhedonia) poor adherence (only 30% of patients during
long-term treatment)
Classification of atypical antipsychotics
specific D2 and D3 antagonists -sulpiride, amisulpiride (f.o. Solian)
serotonin/dopamine antagonists SDA - risperidone (f.o.Risperdal), ziprasidone (f.o. Abifal)
multireceptor targeted antagonists (MARTA) clozapine (f.o. Leponex), olanzapine (f.o.Zyprexa), quetiapine (f.o. Seroquel), zotepine (f.o. Zoleptil)
Atypical antipsychotics (new APs, 2nd generation APs )
Advantages of atypical antipsychotics
Better efficacy:
in treatment-resistant patients +(+)
in negative symptoms ++
in neuropsychological deficits ++
no clinically relevant motor side effects +++
Fewer affective side effects +(+)
Better adherence ++
Better subjective well-being and quality of life ++
Classification of atypical antipsychotics - receptor binding affinities
Drug D2 5HT2 Alfa 1 H1 M
SulpirideAmisulpiride
++(+)
Ziprasidone + + +
Risperidone + + + <+
Quetiapine + + + +
Zotepine + + + + <+
Olanzapine + + + + +
Clozapine + + + + +
Depot antipsychotics
Benefits of depot (long-acting) injections:optimise treatment adherence (reduce relapse)assure delivery, avoid first-pass metabolismuse lowest effective dose, predictable plasma levels simple administration, regular contact with team Available depot APs: fluphenazine decanoate/enanthate flupenthixol decanoate, haloperidol decanoatezuclopenthixol decanoate, oxyprothepin decanoate available depot atypical APs -Risperdal Consta
relapse rates are lower with continuous
antipsychotic therapy !relapses with APs signif. lower than with
placebo (circa 20% vs 50%)poor adherence leads to relapse and high
costs to individuals, families, carers and society
stopping medication is the most powerful predictor of relapse
Mechanism of action
all available clinically effective APs block D (dopamine) receptors, the potency to reduce psychotic symptoms is most closely correlated with the affinity to D2 receptor
others systems may play important role (glutamate, noradrenaline, serotonin, GABA, neuropeptides)
atypical APs differentially affect other systems (serotonin) - more specific pharmacological action generally safer, better tolerated
APs differ in their ability to block the various receptors - e.g. in their side effects profiles, but no in their therapeutic profiles
Mechanisms of actionAll the known APs share the common property of
blocking DA receptor:blockade of DA receptors in the nigrostriatal DA
pathway - a drug-induced parkinsonismblockade of DA receptors in the mesolimbic DA
pathway - antipsychotic efficacy (especially positive symptoms)
blockade of DA receptors in the mesocortical DA pathway - blunting of emotions and cognitive side effects
blockade of DA receptor in tuberoinfundibular DA pathway - elevation of prolactin levels
Mechanism of action - dopaminergic pathways of the CNS
Stahl SM.: Essential Psychopharmacology, 2000
Pharmacokinetics
most APs have high binding to plasma protein, volume of distribution, and lipid solubility
the most important clinical generalisation is that all the APs can be given in a one daily dose once patient is in a stable condition
APs are metabolised in the liver and reach steady plasma levels in 5-10 days.
Doses (and dose equivalence of atypicals)
180120 – 180140 – 18080 – 160100 – 160 Ziprasidone
3015 – 2015 – 3010 – 2010 – 20 Aripiprazole
950400 – 750500 – 800300 – 600350 – 700 Quetiapine
4012.5 – 22.515 – 2510 – 2010 – 20 Olanzapine
850300 – 550400 – 600250 – 500300 – 500 Clozapine
Atypicals
Maintenance treat.
(mg/day)
Acute treat.
(mg/day)
Maintenance treat.
(mg/day)
Acute treat.
(mg/day)
Highest final acute dose
(mg/day)
Multi-episode patientFirst-episode patient
Medication
10.53.5 – 5.54 – 6.52 – 4.52.5 – 5 Risperidone
115Partial response to treatment
63Little or no response to treatment
Maximum number of weeks to wait
Minimum number of weeks to wait
Duration of treatment
104Partial response to treatment
63Little or no response to treatment
Maximum number of weeks to wait
Minimum number of weeks to wait
Inadequate response to initial antipsychotic
Inadequate response to second antipsychotic
Side effects
Acute extrapyramidal side effects:parkinsonian syndromeacute dystoniaakathisia
Tardive dyskinesia (new antipsychotics 0.6%
vs haloperidol 5.3%)
Neuroleptic malignant syndrome (NMS)
Side effects
Autonomic side effects:anticholinergic (blurred vision, dry mouth, constipation,
urine retention)hypersalivation
Cardiovascular effects:orthostatic hypotensioncardiac rhythm disturbances
Dermatological and ocular effects
Endocrine effects
Hepatic effects
Haematological effects
Side effects
Metabolic side effects:hyperprolactinemiaweight gaindiabetesdyslipidemia
QTc prolongation
Hyperprolactinemia
Prolactin (PRL): Pituitary hormone involved in lactation, learning, body temperature, immune response, cortisole secretion
normal values: 5 - 25 ng/ml (or U/l) in men and non-pregnant and non-lactating women
prolactin-related side effect: galactorrhoea, amenorrhea, sexual dysfunction
PRL is elevated by: D2 blockers (antipsychotics) sleep, stress, exercise, sexual activity, food, pituitary lesions, seizure disorder, renal/hepatic disease, hypothyroidism
Side effects - hierarchy ofantipsychotic weight gain (10 weeks)
Mea
n c
han
ge
in b
od
y w
eig
ht
(kg
)
(Allison DB et al. Am J Psychiatry 1999;156:1686–96)
5
4
3
2
1
0
–1
Place
bo
Molin
done
Zipra
sidone
Fluphen
azin
e
Haloper
idol
Non-phar
m c
ontrol
Risper
idone
Chlorp
rom
azin
e
Sertin
dole
Thiorid
azin
e
Olanza
pine
Cloza
pine
Hierarchy of weight gain but also differential rate (trajectory) and total gain (plateau)
drug Weightgain
Risk fordiabetes
Worseninglipidprofile
Clozapine +++ + +
Olanzapine +++ + +
Risperidone ++ D D
Quetiapine ++ D D
Aripiprazol +/- - -
Ziprasidon +/- - -
D discrepant results Diabetes Care, 27, 2004, 2, 596-601
Consensus development conference on antipsychotic drugs and obesity and diabetes (American diabetes association, APA, American Association of clinical endocrinologists, North American Association for the study of obesity).
-5
0
5
10
15
20
25
30
35
40
Zipr.160 mg
Risp.16 mg
Olan.20 mg
Seroq.750 mg
Thior.300 mg
Halo.15 mg
(n=24) (n=25) (n=27) (n=27) (n=31) (n=30)
Adverse effects - QTc prolongation
Mean changeof QTc(msec)
Pfizer Study 54
Indications
schizophrenia disorderdelusional disordermood disorders with psychotic symptomspsychosis secondary to nonpsychiatric medical
condition or substance-induced condition
References : Allison DB, Mentore JL, Moonseong H.: Antipsychotic-induced
weight gain: a comprehensive research synthesis. Am. J. Psychiatry, 156, 1999, pp. 1686-1696
Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care, 27, 2004, 2, pp. 596-601
Janicak PG.: Handbook of psychopharmacology, Baltimore: Williams and Willkins, 1999
Kaplan HI, Sadock BJ, Grebb JA.: Kaplan and Sadock´s synopsis of psychiatry, Baltimore : Williams and Wilkins, 1997
Stahl, SM.: Psychopharmacology of antipsychotics, London: Martin Dunitz, 1999
Stahl SM.: Essential Psychopharmacology, Cambridge: Cambridge University Press, 2000