Antipsychotics Flashcards
Dopamine pathways and action of antipsychotic
- Mesocortical: VTA to FC->Stereotypic behaviour and cognition ->D2 blockade, may worsen negative symptoms, +5HT block increases DA (improved -ve) 2. Mesolimbic: VTA to amygdala and NAc->Limbic system ->D2 blockade, treating +ve symptoms 3. Nigrostriatal: SN to striatum->Movement’ ->D2 blockade= relative ACh excess->EPS 4. Tuberphypophyseal: VHypothalamus to median eminence->Prolactin secretion 5. CTZ->Vomiting
Dopamine role in schizophrenia
- Positive symptoms= ++Dopmine in mesolimbic
- Negative symptoms= -ve DA in mesocortical
NMDA R hypofunction function/role
- Mesolimbic= disinhibition by GABA, NMDA on GABA interneurons
- Mesocortical= -ve ++of DA postsynaptic neruons
Explanation of side effect origin
- Motor-> nigrostriatal
- Prolactin->tuberohypophyseal (loss of inhibition)
- Loss of pleasure->Reward of mesolimbic
- Antimuscarinic->balance of DA and Ach in striatum. -ve DA = ++ACh= EPS, antimuscarinic = -ve EPS + constipation, urinary retention, dry eyes
- Alpha adrenoR->hypotension and sedation, impotence, failure to ejaculate
- Serotonin 2 A antagonism->++DA and Glu at mesocortical= reduces negative symptoms. At nigrostriatal= disinhibition +DA->-ve EPS. At mesolimbic->-ve ++in DA->less positive symptoms
- Antihistamine->sedation and weight gain 8. Metabolic/CV risk
First generation typicals
- Haloperidol
- Flupenazine
- Chlorpromazine
- Flupentixol
Second generation atypicals
- Sertindole
- Clozepine
- Quetiapine
- Aripiprazole
- Amisulpride
- Risperidone
Drug with ++side effects, +effect on negative symptoms
Clozepine
Less weight gain
- Amisulpride 2. Aripiprazole 3. Asenapine 4. Sertindole
More sedating and weight gain, hyperlipidemia
Clozepine Olanzepine
High prolactin
- Paliperidone
- Risperidone
- First generation
QTc prolongation
- Sertindole
Orthostatic hypotension
- Risperidone 2. Paliperidone
Indications
- Schizophrenia and other psychotic disorders
- Mood disorders with/without psychosis
- Violent behaviour
- ASD
- Tourettes
- Somatoform
- Dementia
- OCD
Onset
Immediate calming effect and decrease in agitation
Thought disorder responds in 2-4 weeks
Rational use
- Do not combine
- All are equally effective, except for clozepine
- Atypicals are as effective and have better side effect profile
- Choose a drug the patient has responded to in the past or successful use in a family member
- Route is either daily oral or IM
- Duration is minimum of 6 months, usually for life.
Dosing
- Start at low dose, then titrate every 2-4 weeks to maximise safety and minimise side effects
Advantages and disadvantages for clozapine
- Advantages: Most effective for treatment resistant.
a. Does not worsen tardive symptoms
b. 50% benefit, especially those with paranoid - Disadvantages: a. Drowsy b. sedation c. hypersalivation d. tachyC e. dizziness f. EPS g. NMS h. 1% agranulocytosis i. myocarditis
Side effects
- Anticholinergic:
Dry mouth, urinary retention, constipation, blurred vision, toxic-confusional states
- α-adrenergic blockade Orthostatic hypotension, impotence, failure to ejaculate
- Dopaminergic blockade: Extrapyramidal syndromes (dystonia, akathisia, pseudoparkinsonism, dyskinesia), galactorrhea, amenorrhea, impotence, weight gain
- Anti-histamine: Sedation Hematologic Agranulocytosis (clozapine)
- Hypersensitivity reactions: Liver dysfunction, blood dyscrasias, skin rashes, neuroleptic malignant syndrome, altered temperature regulation (hypothermia or hyperthermia)
- Endocrine: Metabolic syndrome
Anticholinergic SE
Red as a beet Hot as a hare Dry as a bone Blind as a bat Mad as a hatter
Counselling in clozapine
- You will need to have regular blood tests and other checks while taking clozapine to help your doctor look out for serious side effects. Before starting treatment you will need CBC w/ neutrophil count, BMI, waist circumference, Fasting lipids, Fasting sugars, HbA1C, Anticonvulsant levels if appropriate, Baseline ECG.
Most important risks are agranulocytosis, myocarditis, metabolic syndrome
- CV risk- we will monitor your BP, BMI, glucose, lipids, waist circumference.
- Recommend healthy lifestyle to avoid ++risks.
- Taking your antipsychotic medicine regularly is important: because stopping or taking it irregularly is associated with high risk of relapse and suicide in order to prevent an episode, rather than taking it after symptoms occur.
- Consider whether a regular injection may suit you better than taking tablets.
- It is best to avoid using illicit substances because: even intermittent use of cannabis or amphetamine markedly decreases control of psychotic symptoms regular use of illicit drugs increases risk of relapse.
- Make sure you understand:
a. what extrapyramidal side effects are and what you can do about them
b. the risk of tardive dyskinesia with long-term antipsychotic treatment. - This medicine may cause drowsiness and may increase the effects of alcohol, cannabis or sleeping tablets. Do not drive or operate machinery if you are affected.
- You may feel dizzy on standing when taking this medicine. Get up gradually from sitting or lying to minimise this; sit or lie down if you become dizzy.
Adverse effects of clozapine
- Common (>1%)
drowsiness (occurs in 40%), hypersalivation (can cause aspiration pneumonia), constipation (may result in obstruction, paralytic ileus and death), seizures, headache, tachycardia, hyperpyrexia (5%), hepatitis, neutropenia, vomiting, urinary incontinence, nocturnal enuresis
- Infrequent (0.1–1%) myocarditis (usually in the first month of initial treatment but rarely may occur when starting after a break in treatment), agranulocytosis, eosinophilia, priapism, EPSE
Clozapine workup and follow up
- General and CV health
- CBC w/ neutrophil count
- BMI, waist circumference
- Fasting lipids
- Fasting sugars, HbA1C
- Anticonvulsant levels if appropriate
- Baseline ECG
- May consider CRP and troponins
Titration: frequent BP
Day 7, 14, 21: ECG, cardiac enzymes + CK, FBC, wt, BP
Weekly until 18 weeks, then monthly: FBC, BP, weight
3-6: Echo, fasting lipids, fasting glucose
6 monhts: weight, fasting lipids, fasting glucose, ECG
Annual: ECG, full physical, fasting lipis and glucose, wt
Monitoring WCC in clozapaine
- Weekly during the first six months of clozapine administration
- Every other week for the second six months
- Every four weeks after one year, for the duration of treatment
- For an additional month after clozapine is stopped
CV monitoring in clozapine
- Risk of myocarditis which can worsen rapidly
- This should include assessment of clinical status for subjective signs of distress, vital signs each visit, electrocardiogram at baseline, and then weekly laboratory tests including:
●Eosinophil count
●Sedimentation rate or C-reactive protein
●Troponins
Metabolic and GIT monitoring
- Monthly lipids, glucose, BMI, BP, waist
- Prophylactic stool softener for constipation
Antipsychotic metabolic monitoring
- Baseline
Wt, ht, BMI, BP
ECG, Prolactin, FBC, UEC, LFTS, fasting lipids, fasting glucose, TFTs, bHCG
- First 2-3 weeks: weight, BP
- 3, 6 months: wt, LFTs, lipids, glucose, ECG
- Long term 6 monthly: wt, BMI, BP
- Annual
Wt, BMI, BP
Full physical
FBC, UEC, LFTs, fasting lipids, fasting glucose, ECG
