clinical pharmacology and neurosciences Flashcards
What is the CATIE study?
Study was a nationwide clinical trial that compared the effectiveness of older (first available in the 1950s) and newer (available since the 1990s) antipsychotic medications used to treat schizophrenia.
what happened in phase 1 of CATIE study
Phase 1: Phase I compared old and new antipsychotics.
Four of the newer medications to one another, and to an older medication
which four newer and which older antipsychotic were used in which phase of CATIE study
Phase 1
olanzapine
quetiapine
risperidone
ziprasidone
or to the older, ‘typical’ medication:
perphenazine
what did the CATIE study phase 1 show?
high rates of discontinuation due to intolerable side-effects or failure to adequately control symptoms.
olanzapine, was slightly better than the other drugs but also was associated with significant weight-gain as a side-effect. Patients assigned to olanzapine had the longest successful treatment time, and the fewest hospitalizations as a result of exacerbation of schizophrenia.
Surprisingly, the older, less expensive medication (perphenazine) used in the study generally performed as well as the four newer medications.
Contrary to expectations, movement side effects (rigidity, stiff movements, tremor, and muscle restlessness) primarily associated with the older medications were not seen more frequently with perphenazine than with the newer drugs.
what did PHASE 2 of CATIE trial aim to look at?
what were the study arms?
Phase II
To provide guidance on which antipsychotic to try next if the first failed (either due to ineffectiveness or intolerability).
Participants who discontinued their first antipsychotic medication because of :
1. inadequate management of symptoms —> efficacy (clozapine) pathway
- intolerable side effects–> tolerability (ziprasidone) pathway.
which medication was found to be effective in phase 2 of catie trial/
Clozapine was remarkably effective and was substantially better than all the other atypical medications.
what else did the catie study look at?
risk of metabolic syndrome
Central obesity: waist circumference 102 cm or 40 inches (male), 88 cm or 36 inches(female)
Dyslipidaemia: TG 1.7 mmol/L (150 mg/dl)
Dyslipidaemia: HDL-C < 40 mg/dL (male), < 50 mg/dL (female)
Blood pressure 130/85 mmHg
Fasting plasma glucose 6.1 mmol/L (110 mg/dl)
MS at baseline in the CATIE group was 40.9%
How are anti-psychotics categorised
typical (first generation)
atypical types (second generation)
which other receptor does atypical work on and which medications
5-HT1a agonism (some such as clozapine, quetiapine, ziprasidone)
which are typical and atypical?
Typical antipsychotics Atypical antipsychotics
Chlorpromazine Clozapine
Flupenthixol Risperidone
Zuclopenthixol Olanzapine
Perphenazine Quetiapine
Trifluoperazine Ziprasidone
Sulpiride Amisulpride
Haloperidol Aripiprazole
how to antipsyhotic works?
reduce dopaminergic neurotransmission.
mechanism of typical anti-psychotics
defined by the ability to block dopamine (D2) receptors.
They also have in, varying degrees, M1, Alpha-1 and H1 receptor blockade.
mechanism of atypical antipsychotics
D2 and 5-HT2a antagonism
Rapid D2 dissociation
how else can anti-psychotics be classified
by structure
which medication is Phenothiazines (Aliphatic side chain) associated with
Phenothiazines (Aliphatic side chain) Chlorpromazine
which medication is Phenothiazines (Piperidine side chain) associated with
Thioridazine, pipothiazine
which medication is Phenothiazines (Piperizine side chain) associated with
Trifluoperazine, fluphenazine
Flupenthixol, zuclupenthixol -which structure is associated with these medications
Thioxanthenes
what structure is haloperidol associated with
Butyrophenones
Pimozide - which structure is associated with this medication
Diphenylbutylpiperidines
which structure is associated with this medication
quietapine
sulpiride/amirsulpride
aripiprazole
Dibenzothiazepines Quetiapine
Substituted benzamides Sulpiride, amisulpride
Arylpiperidylindole (quinolone) Aripiprazole
which structure is associated with this medication
Clozapine
Risperidone
olanzapine
Dibenzodiazepines Clozapine
Benzoxasoles Risperidone
Thienobenzodiazepines Olanzapine
what classification is cloazapine
what is it a deriative off
atypical antipsychotic
used when antipsyhotics trialled and failed
classified as a tricyclic dibenzodiazepine derivative.
where is clozapine more active
in limbic system rather than striatal
which receptors does clozapine work on?
Clozapine is a D1 (dopamine 1), D2, 5-HT2A, alpha1-adrenoceptor, and muscarinic-receptor antagonist.
It has a particularly high affinity for the D4 receptor and exerts only a weak blockade of D2 receptors.
clozapine impact on prolactin
nil to little
Receptors affected by clozapine
Receptors affected by clozapine
Dopaminergic
Histaminergic
Serotonergic
Adrenergic
Cholinergic
what metabolises clozapine
cYP1A2.
what can impact clozapine levels
acco smoke contains polycyclic aromatic hydrocarbons
induce CYP1A2
what is an inhibitor of this cytochrome
what affect does it have on clozapine level
CYP1A2
coffeee
caffeine (as inhibitor) of cyp1a2
this leads to increased cloazpine level
list the inducers and inhibitors of this cytchrome
and the impact it has on clozapine level
Drug Effect on plasma clozapine levels
SSRI’s Increased
Erythromycin Increased
Caffeine Increased
Carbamazepine Decreased
Phenytoin Decreased
Tobacco Decreased
another important cytochrome with clozapine
CYP2D6.
medical word for hypersalivation
(silarrhoea).
1/3 of patients develop this
s/e of clozapine
Drowsiness/ sedation
Constipation
Salivation
Weight gain
Dizziness
Insomnia
Nausea
Vomiting
Dyspepsia
active metabolites of clozapine
e main ‘active’ metabolites (note: some sources regard the metabolites as inactive) are:
N-desmethylclozapine (norclozapine)
clozapine N-oxide
complications of clozapine
Agranulocytosis
Myocarditis, pericarditis / pericardial effusion, cardiomyopathy
Seizures
Severe orthostatic hypotension with or without syncope
Increased mortality in elderly patients with dementia related psychosis
Colitis
Pancreatitis
Thrombocytopenia
Thromboembolism
Insulin resistance and diabetes mellitus (Approx 33 percent developed diabetes mellitus over a ten year period (Henderson, 2005))
what is used to help manage excess salivain clozapine patients
Amisulpride (supported by placebo controlled RCT)
Atropine (rarely used)
Hyoscine hydrobromide (widely used but no published data)
Amitriptyline
Propantheline (two Chinese RCTs, one positive)
Benzhexol (small open study suggests useful)
caution with clozapine
prostatic hypertrophy
susceptibility to angle-closure glaucoma
adult over 60 years
what shoudl be noted in patints with seizures on clozapine
Seizures:
When using clozapine, valproate should be considered if
Using high doses
Plasma levels > 0.5 mg/l
Patient experiences seizures
facts about myocarditis with clozapine
Myocarditis is rarely seen in clozapine use but carries with it a high mortality.
1 in 500 rate,
early in the course of clozapine treatment. detected within 16 days (median) of initiating clozapine in a study of 116 cases (Hass, 2007).
Approximately 80 percent of cases of clozapine-induced myocarditis occur within four weeks of drug initiation
90 percent occur within eight weeks.
Post-mortem examination - damaged myocytes and eosinophilic infiltration suggesting a type I Ig E-mediated acute hypersensitivity reaction.
Subsequent use of clozapine in cases with clear clozapine-induced myocarditis leads to recurrence of myocarditis in most cases when the drug is restarted.
Features include:-
Fever
Chest pain
Tachycardia
Dyspnoea
Flu-like symptoms
Elevated eosinophil count
Elevated cardiac enzyme levels
biomarkers for myocarditis
Biomarkers, including creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), myoglobin, and troponin, may all be raised in patients with myocarditis. Troponin T and I are the most specific as they are unique to the myocardium (troponin C is synthesised in skeletal muscle). That said, they are not raised in every case and so often a range of markers are assessed.
monitoring clozapine
Clozapine requires differential white blood cell monitoring weekly for 18 weeks, then fortnightly for up to one year, and then monthly as part of the clozapine patient monitoring service.
prolactin at 6 months but unlikely to eb raised - be more vigilants for symptoms
lood lipids and weight should be measured at baseline, at 3 months (weight should be measured at frequent intervals during the first 3 months), and then yearly with antipsychotics. Patients taking clozapine require more frequent monitoring of these parameters: every 3 months for the first year, then yearly.
Fasting blood glucose should be measured at baseline, at 4–6 months, and then yearly. Patients taking clozapine should have fasting blood glucose tested at baseline, after one months’ treatment, then every 4–6 months.
he gold standard for diagnosis of myocarditis is
an endomyocardial biopsy,
suggested mechanisms of weight gain with clozapine
suggested mechanisms (Dayabandara, 2017) include (presumably mediated through stimulation of appetite):
5HT2a and 5-HT2c antagonism
D2 and D3 antagonism
H1 and M3 antagonism
Hyperprolactinemnia
Increased serum leptin (leading to leptin desensitisation)
Ghrelin
which antipsychotics are at high moderate weight gain risk
Clozapine High
Olanzapine High
Chlorpromazine Moderate
Quetiapine Moderate
Risperidone Moderate
Paliperidone Moderate
if no improvement with lifestyle changes, which antipsyhotics have good support with switching
aripiprazole
ziprasidone
lurasidone
what is good augmentation for clozapine induced weight
Liraglutide
which anti-pschotic is associated with death
Thioridazine has pronounced effects on K+ channels and materially prolongs the QTc interval, it is most associated with sudden death.
which antipsychotics have highest risk of diabetes
what should be considered in prediabetics
Clozapine and olanzapine are associated with the highest risk.
Amisulpride, aripiprazole, and ziprasidone are recommended by the Maudsley for patients with a history or predisposition for diabetes.
which antipsychotics showed EEG changes
Clozapine 47.1%
Olanzapine 38.5%
Risperidone 28.0%
Typical antipsychotics 14.5%
Quetiapine 0.0%
what is the steady state with relation to antipsychotics
point at which the amount of drug administered each day is exactly counterbalanced by the amount eliminated.
s. Steady-state is when the administration of a drug and the clearance are balanced, creating a plasma concentration that is unchanged over time
what are the half life of the following antipsychotics
Antipsychotic
Amisulpride
Aripiprazole
Quetiapine
Olanzapine
Clozapine
Risperidone
Ziprasidone
Aripiprazole 75 hours
Olanzapine 30 hours
Risperidone 20 hours
Clozapine 12 hours
Amisulpride 12 hours
Ziprasidone 7 hours
Quetiapine 6 hours
what are the times to steady state for the list of anti psychotics
aripiprazole 2 weeks
olanzapine 1 week
the rest 2-3 days
which anti psychotics cause postural hypotension
Risperidone
Clozapine
Olanzapine
Paliperidone
Quetiapine
Ziprasidone
which anti psychotic should be considered if postural hypotension
Amisulpride
Aripiprazole
Haloperidol
Sulpiride
Trifluoperazine
which psychiatric drugs interact with contraceptives
St John’s Wort
Carbamazepine
Phenytoin
Topiramate
Barbiturates
reduced contraceptive effect
porphyria symptoms
Abdominal pain
Mental state changes
Constipation
Vomiting
Muscle weakness
red brown urine
seizure
anxiety
hypertension
palpitations
what are porphyrias
orphyrias are a group of uncommon disorders that are caused when there are problems with the production of chemicals called porphyrins in the body. Porphyrins are the chemical building blocks of haem, which form haemoglobin, the component of red blood cells that allows oxygen to be carried around the body. An increase in the amount of a specific porphyrin or a porphyrin precursor results in symptoms of porphyria
which medications can precipitate prophyria
Barbiturates
Benzodiazepines
Sulpiride
Certain mood stabilizers
what are the three phases of steroid use
cycling 4-12 week usage and stopping to minimise side effects
stacking more than one at a time, for muscle growth and strength
pyramiding increase dose to peak then wean
what class of drugs are steriods
class C
what psychiatry conditions are associated with steroid use
mania
anxiety
depression
pscyhosis
mood instability
s/e of steroids
skin -oil skin, acne, male pattern baldness, jaundice
muscle hypertrophy
cardio -raised bp, hr, LDL, MI
Hepatic - cholesterol, malignant liver,
sleep apnoea
abnormal sperm count, menstruation changes, shrink breast tissue, hypogonadism, deep voice, BPH, Testicular atrophy
what is the active metabolite impramine for which antidepressants
lofamriane
impramine
