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Antipsychotic medication. Dr C Kotzé. Introduction. Introduced in 1950’s Decreases relapse significantly Only treats the Sx Not a cure 2 Major classes: Dopamine receptor antagonists (typical) Serotonin-dopamine antagonists (atypical). Dopamine hypothesis. - PowerPoint PPT Presentation
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Antipsychotic medicationAntipsychotic medication
Dr C Kotzé
IntroductionIntroduction
• Introduced in 1950’s
• Decreases relapse significantly
• Only treats the Sx
• Not a cure
• 2 Major classes:– Dopamine receptor antagonists (typical)– Serotonin-dopamine antagonists (atypical)
Dopamine hypothesisDopamine hypothesis
• D2 receptor block improves positive Sx
• Mesolimbic & mesocortical tracts
• Other transmitters : 5HT, NE, GABA, glutamate
Four key Dopamine PathwaysFour key Dopamine Pathways
Mesolimbic pathwayMesolimbic pathway
• Hyperactivity of DA → hallucinations, delusions and thought disorders
• Role in aggressive Sx
• Drugs that ↑ DA → psychotic Sx
• Antipsychotics ↓ DA (blocks receptors)
Mesocortical pathwayMesocortical pathway
• Related to mesolimbic pathway• Projects to different brain areas • DA deficit postulated to have role in
negative & cognitive Sx in schizophrenia• Causes of ↓ DA
– excitotoxic overactivity of glutamate system – 2° to inhibition by excess serotonin– D2 block by antipsychotics
• Degenerative process here could explain worsening of negative Sx over time
Nigrostriatal & TuberoinfundibularNigrostriatal & Tuberoinfundibular
• Nigrostriatal: – part of extrapyramidal nervous system– Controls motor movements– ↓ DA → movement disorders & EPSE
• Tuberoinfundibular: – controls prolactin secretion– DA inhibits prolactin
Acute managementAcute management
• Aggression treated with chemical restraints:lorazepam 2-4mg imi and serenace 5 mg imi or zuclopenthixol-acetate 50-100mg imi
• Decide if admission is warranted / essential
Classes of antipsychoticsClasses of antipsychotics
• Typical (DA)– Block D2 receptors
– E.g. Haloperidol, chlorpromazine
• Atypical (SDA)– Serotonin-dopamine
antagonists – E.g. Clozapine,
risperidone, olanzapine
Dopamine antagonists (typical)Dopamine antagonists (typical)
• Butyrophenone (haloperidol)
• Phenothiazines (chlorpromazine,
trifluperazine, fluphenazine)
• Diphenylbutylpiperidine (pimozide)
• Benzamide (sulpiride)
• Thioxanthenes (flupenthixol, zuclopenthixol)
Dopamine antagonistsDopamine antagonists
• Differ in molecular structure & potency
• Equal efficacy for positive symptoms
• Side-effect profiles differ
• Average dosage: – chlorpromazine 200-600mg– haloperidol 2-6mg– trifluoperazine 20mg
Dopamine antagonistsDopamine antagonists
• Peak concentration:– oral within 1-4 hours– parenteral 30-60 minutes
• ↑ potency associated with – ↑EPSE– ↓anti-Ach– ↓ epileptogenic effect
• DA receptor block is immediate but antipsychotic effect takes weeks
Dopamine antagonistsDopamine antagonists
• D2 block responsible for:– Antipsychotic effect (mesolimbic)– Worsen negative Sx (mesocortical)– Movement disorders & EPSE (nigrostriatal)– Hyperprolactinemia (tuberoinfundibular)
• Also muscarinic cholinergic block– Ach & DA → reciprocal relationship in nigrostriatal
pathway– Excess Ach when DA inhibited– Cholinergic block mitigate effects of D2 block in
nigrostriatal pathway → less EPSE
• Also blocks alpha1 & histaminergic receptors
DA antagonists: side-effectsDA antagonists: side-effects
• Neurological (D2 antagonism):
– Lowers seizure threshold– Extrapyramidal reactions– Urinary incontinence – Dysphagia
• Cognitive (Histaminergic antagonism):– Sedation– Decreased concentration– Depression
DA antagonists: side-effectsDA antagonists: side-effects
• Anticholinergic (Muscarinic R antagonism):– Dry mouth– Blurred vision / dry eyes– Constipation / urinary retention– Cognitive dysfunction
• Cardiovascular (Alpha1 & muscarinic block):– Dizziness, hypotension, syncope,
tachycardia– ECG changes, prolonged QT interval – ↑ risk for sudden death (arrhythmias)
DA antagonists: side-effectsDA antagonists: side-effects
• GI (muscarinic & H1 antagonism):– Weight gain– Constipation, occasionally diarrhea– Vomiting– Difficulty swallowing
• Sexual (D2, Alpha1 & muscarinic block):– Decreased libido– Erectile dysfunction, inhibition of
ejaculation– Anorgasmia
DA antagonists: side-effectsDA antagonists: side-effects
• Endocrine effects: – Increased prolactin (sexual dysfx,
galactorrhea, ↑weight, ↑/↓ glucose, SIAHD)
• Hypersensitivity reactions:– Photosensitivity, skin reactions– Agranulocytosis– Anaphylactic reactions
• Ocular effects: – Retinitis pigmentosa– Lenticular pigmentation
DA antagonists: EPSEDA antagonists: EPSE
• Acute dystonia
• Parkinsonism
• Akathisia
• Neuroleptic malignant syndrome
• Tardive dyskinesia
Acute DystoniaAcute Dystonia
• First 4-7 days• ↑ risk: young males; high potency • Painful contraction of muscles that result in
abnormal movements or posture: – Torticollis– Trismus– Protrusion of tongue– Dysphagia– Laringo-pharyngeal spasm– Oculogyrus crisis
• Biperidine 5mg ivi / imi
ParkinsonismParkinsonism
• Tremors, rigidity & bradikinesia • DA inhibits ACh• If DA receptors blocked → ↑ACh• ↑ ACh associated with ↑ EPS• Rx: Anticholinergics
– Orphenadrine 50mg po 1-3x /d or – Biperidine 2mg 1-3x /d
• Always try to lower dosage of antipsychotics• If severe, replace with SDA
AkathisiaAkathisia
• Develops within 1st few weeks
• Subjective tension & anxiety combined with objective restlessness
• Unable to sit still, fidgets, rocks, paces
• Lower dosage if possible
• B-blockers: Propanolol 10-30mg tds
• Benzodiazepine
• Change to low potency typical or SDA
Neurolept Malignant SyndromeNeurolept Malignant Syndrome
• Mostly in 1st week; 10-30% mortality• Muscle rigidity & fever with 2/ > of following:
– Diaphoresis– Autonomic instability (labile BP/ tachycardia)– Tremor– Dysphagia– Mutism– Incontinence– Leukocytosis– Change in level of consciousness – Lab evidence of injured muscle: ↑ CK
NMS: ManagementNMS: Management
• Emergency (ICU); stop all anti-psychotics• Cool pt off, aggressive hydration• Monitor vitals, nasogastric tube • Diazepam or lorazepam • DVT prophylaxis• Beware renal failure (↑CK / myoglobin)• Dantrolene 3-5mg/kg IV in divided dose• Bromocriptine 5mg qid (? L dopa)• If no response : ECT• Rechalenge: low dose, atypical, ECT
Tardive dyskinesiaTardive dyskinesia
• Appears very late (>4 years); irreversible• Risk factors: Female, elderly, ↑dosage,
• Up-regulation of D2-R in nigrostriatal pathway
• Abnormal involuntary movements:– Oral movements, protrusion of tongue, grimaces– Choreoatesosis of extremities & abN postures
• Not alleviated by antichol / antiparkinsons drugs
• Reduce dose, stop anticholinergics• Try SDA / clozapine
Serotonin – dopamine Serotonin – dopamine antagonists (atypical)antagonists (atypical)
• Clozapine (Leponex, Cloment)
• Risperidone (Risperdal)
• Olanzapine (Zyprexa)
• Quetiapine (Seroquel)
• Aripiprazole (Abilify)
• Ziprasidone (Geodon) • Amisulpride (Solian) (Selective D2/3
antagonist)
SDAsSDAs
• 5HT2A-D2 antagonists
• Serotonin inhibits DA release
• Strongest inhibition in nigrostriatal pathway
• Blocking 5HT here promotes DA release → ↓ movement disorders
• Serotonin fails to reverse D2 antagonism in mesolimbic pathway
SDAsSDAs
• Side-effects depend on relative receptor affinities: DA, NA, H1, Ach
• Usual daily dosages:
• Olanzepine 5-20 mg /d p.o.
• Clozapine : 75-600mg / d p.o.
• Risperidone : 2-6mg / d p.o
• Sulpiride : 600-800mg / d p.o
SDA: IndicationsSDA: Indications
• Severe side-effects such as EPSE• Tardive dyskinesia• Young person with first episode• Better treatment for negative symptoms (?)• Treatment-resistant : clozapine• Rechallenge after NMS• Unacceptable prolactin levels• Mood symptoms and ↑ suicide risk• Elderly with behavioral symptoms
SDA: Side-effectsSDA: Side-effects
• Neurological (D2 antagonism): – Lowered seizure threshold (esp clozapine)– EPS (low risk); Dysphagia– Urinary incontinence
• Cognitive (H1 antagonism):– Headache & sedation (esp in 1st 2 weeks)
• Anticholinergic (Musc-antagonism):– Dry mucous membranes; Blurred vision – Constipation; Urinary retention
SDA: Side-effectsSDA: Side-effects
• Cardiovascular (Alpha1 & Ach block):– Hypotension, tachicardia– T-wave inversion, ST segment depression– Prolonged QT interval, sudden death– Cardiomyopathy (Clozapine)
• GI (5HT2c & H1 block):– Weight gain & metabolic syndrome
(worst: clozapine & olanzapine)– Constipation (severe with clozapine)– Sialorrhea (esp clozapine)
SDA: Side-effectsSDA: Side-effects
• Endocrine – ↑ Prolactin (esp risperidone)– Hyperglycemia
• Changes in temperature regulation
• Sexual (D2, Ach, Alpha1, 5HT block)
• Ocular: Lens changes with Quetiapine• Hypersensitivity reactions:
– Transaminase↑ & Hepatic dysfx (rare)– Pancreatitis – Agranulocytosis (esp clozapine in first 6 months)
ClozapineClozapine
• Only for treatment resistant cases
• Highest risk for agranulocytosis, weight gain and metabolic syndrome
• Sialhorrhea, constipation, sedation & convulsions
RisperidoneRisperidone
• ↑ risk for EPSE with high dosages
• ↑ prolactin with galactorrhea
OlanzapineOlanzapine
• High risk for weight gain, metabolic syndrome and sedation
• Increases AST
Metabolic Syndrome Metabolic Syndrome (Syndrome X)(Syndrome X)
• Abdominal circumference >102 cm in men >88cm in women (BMI ≥ 30kg/m²)
• Triglycerides > 150mg/dl (1.7mmol/l)• HDL cholesterol < 40mg/dl (0.9 mmol/l) in
men and 50 mg/dl (1.0 mmol/l) in females• Blood pressure ≥ 130/85 mmHg• Fasting glucose >110 mg/dl (6.5 mmol/l)• Micro-albuminuria
Metabolic syndromeMetabolic syndrome
• Co-occurrence of interrelated risks including:– Obesity– Insulin resistance– Dyslipidemia– Hypertension – Pro-inflammatory &, pro-thrombotic state
• To continue SDA or not – Life style changes (exercise, stop smoking, diet)– Benefits vs risks
Depot preparationsDepot preparations
• Should not be used until response to oral medication demonstrated
• Lowest possible dose (IMI)– Flupentixol decanoate 20-80mg 2-4 weekly– Fluphenazine decanoate 6.25-50mg 2-4
weekly– Zuclopenthixol decanoate 100-400mg 2-
4weekly– Risperidone 25-50mg 2 weekly
General principlesGeneral principles
• Start treatment early
• Gradual increase of dose
• Use lowest effective dose
• Sufficient time (4-6 w)• Prolonged use of prophylactic treatment
(1st episode = 2 yrs; 2nd episode = 5 / > yrs)
• Non-compliance: long acting depot injections
Thank youThank you