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
trazado has an active metabolite named as
MEPP
who termed antidepressant
Lune
which antidepressant most effective by buccal route
fluoxetine
which medication give IM has mood evkvating effects
flupentixol
what is the concern with citalopram in overdose
torasades de pointes
which anti depressant is best for diabetes
SSRI
worst antidepressant for discontinuation symptoms
paraxotine
venlafaxine
best antidepressant for narcolepsy
clopramine
best for bulimia
fluoxotine
best antidepressant for phobias
clopramine
best antidepressant also used for nocturnal enuresis
amitruplline
impramine
which depo is good for preventing relapse
zuclopenthixol
but high risk of s/e
which are the three atypical antipsychotics
OLANZAPINE
ARIPIPRAZOLE
RISPERDONE
lowest dose for haloperidol
25mg
lowest dose for zuclopenthixol
100mg
what is post injection syndrome
when antipsychotic is injected into the BV directly
person will feel sleepy, confused, anxiety, dizziness
lowest dose for flupentixcol
20mg
what are the main EPSE
dystonia
tardive dyskenesia
akathasia
pseudoparkinsonism
facts about dystonia
multiple types
rf: male, neuroleptic naive
10% of patients
usually within mins or hours
what can be given to counteract dystonia
botox
anticholingerics
which EPSE is most resistant to treat
what is it
akathisia
intense sensation of unease or an inner restlessness that usually involves the lower extremities.
where do EPSE act on
D2 receptors in basal ganglia
triad for Parkinsonism
rigidity -cogwheel
bradykinesia
fine tremor -pin rolling
how common is akathisia
25%
what can be used to counteract akathisia
cyprohepadine
benzo
clomidne
propanolol
mirtazpine
whats risk factor for tardive dyskinesia
elderly
female
Early EPSE
what can be used to manage tardive dyskinesia
stop any anticholingeric
gingko. biloba
Tetrabenazine
name some anticholingerics
procyclidine
benztropine
orephradine
which antipsychotic has the longest half life
aripiprazol 75 hours
2 weeks
which depo is good at prevent relapses
zuclopehtnixol
but has s/e lots
what is used to monitor sexual dysfunction?
arizona sexual experience scale
what is pharmacodyanmics
impact of drug on the body
biological
MoA
interactions
receptor binding
what is pharmokinetics
body on drug
Absorption
distribution
Metabolism
elimination
highest rate of priapism
trazaone
chlorapromazine
**
what are anabolic steriods
synethic derivatives of testosterone
they have androgenic properties -masculising
anabolic -tissue building
which type of steriods are anabolic mostly and what is the reason for this
to reduce adrengic impact
such as nandrolone
oxandrolone
aim is for tissue building
wwhat are the functions seen with testosterone
muscle repair amd metabolism
sexual cognition function
bone/lipid metabolism
erythropeosis
who discovered forced swim test snd why
porsolt
preclinical research looking at depression in rats
found those who had antidepressants had more motivation when placed in water
Which antidepressants can be given IV
citalopram
mirtazpine
amitripylline
clomipramine
what can be given IM with a mood elevating affect
flupenthixol
active metabolite of trazdone
MCPP
active metabolite for venlafaxine
o-desmethyl-venlafaxine
which antidepressant can cause cardiac issue in overdose
what is the consequence of thisn
citalopram
torsades des pointes
which two antidepressants have the worst s/e with stopping
paroxtine
venlafaxine
which depo is good at preventing relapses but whats the issue with it
zuclothopenthixol
increased side effects
what is the good thing about fluthixpentol,
can be used in higher doses
minimium effective doses for antipsychotics
halopderiol
zculopehthixol
flupenthixol
pipothazine
fluphenzine
halopderiol - 25mg
zculopehthixol 100mg
flupenthixol 20mg
pipothazine 25mg
fluphenzine 12.5mg
whare are the antidopaminergic s/e
gyanecomastica
galactthorea
reduced sperm count
reduced libidio
ataxia
dizziness , TD, akathasia
what are the anti histamien s/e
sedation drwosy
weight gain
what are anti adregenic s/e
postural hypotension
ejaculation failure
anti cholingeric s/e include
dry mouth
blurred vision
constipation
urinayr retention
etc
worst antipsychotic for weight gain
worst for EPSE
EPSE - haloperidol
weight gain - olazapine, sedation and diabetes
clozapine also weight gain, sedation wg, diabetes
which three antipsychotics dont affect sexual dysufctnion
aripiprazole
lurasidone
aseniapine
what are barbituates
faciitates GABA-A
and prolonngs opening of chloride chanells
how does baritbuates differ from benzo
benzo increases frequency of chanells
how do u remember the difference between barbituates and benzo
BARBIDURATION
FRENZODIAZPINE
WHAT ARe the two phases of obtaining a biogenic amine from an AA
phase 1: oxidation p450 reduction, hydrlosis
phase 2: hydrophilic group added and toxic intermidate is formed then needs to be transferred
name some things in phase II
glucuronidation (most common)
methylation
acetylation
sulfation
conguation with gluthathione
conjucton with amino acids
what occurs in phase III
ATP binding caseette
activation transport for elimination
which is the most common method for phase ii
glucourindation
what is carbamazepine used for
1st line for parital seixures
bipolar and neuropathic pain
who should carbamazepine be ci IN
previous bone marrow suppression
MAOI usage combination
what is charles bonnet syndrome
they have visual hallycinations and auditory
rf : AGE, female, isolated, visual impaiared
associated with mascular degeneration
what are the new IV anti demenetia medications mechanism
IV adicanumab
DISEASE MODIFYING MEDICATIOn in traits
with by degrate the plques by using losomones and phagycotysosis
also lecaneumab
how does ristavigamine and galanatamine differ from donzpezil
galantamine has nictone receptor activity
rivastigmine -also has butylcholsterine
can be patches
half life of donepzil.
70 hours
what can affect a medications ability to function
if it is impaired by air or moisture or klight
for example zopiclone should not be playced in moisture or light
what is used for absent seizure
ethosuximide
blockss t type calcium channels
what is the half life of lithium
4-6 days
half life of rispoderone depo
6-8 weeks
what is the half life of olanazapine
7 days
what is the half life of TCA
2-3 days
what are risk factors for cluster headaches
symptoms
male:female 5:1 , smokers
pain 1/2 times a day lasting 15 mins to 2 hours
intense pain
one side around eye
eye symptoms sometimes such as swelling, redness, ptosis
how do u manage cluster headaches acutely
o2 , nasal subcut triptan
prevention of cluster headaches
prednisolone
verpamil
mx of parxoymal hemioma
indomethacin
which nerve ellicts the papillary light reflex
optic
oculomotor
which nerve ellicit accomodation
optic and oculomotor
jaw jerk which nerve ellicit
trigeminal
which nerve ellicit corneal reflex
trigmeinal and facial
which nerve ellicit gag reflex
glossopharyngeal and vagus
what is PrPc and PrPsc
Prion diseases are associated with the conversion of the α-helix rich prion protein (PrPC) into a β-structure-rich insoluble conformer (PrPSc) t
kuru dx
associated with cannibalism
papa new guniea ate dead ancestors
leads to tremors and loss of coordination from neurodegeneration.
CJD
Creutzfeldt-Jakob disease
prior disease
two types - sporadic and variant
what are the differences in the two types of CJD
variant
younge age 20-30s
longer duration
pulvinar sign in 75%
behavioural/MH changes
EEG waves not usually present
spordiac
older
60s
shorter duration
no pulvinar sign but EEG signs
which of the CJD are more common
sporadic
85%
older adults
which chromosone is associated with prion protein
chromosone 209
methionine homogeneity
coldon 129
what is Gerstmann–Sträussler–Scheinker syndrome
extremely rare
inherited
within families few in world
autosomal dominant
prion disease
with slurred speech, nystagmus and rigitity/spacity/blindness
what are macroscopic changes seen with LBD
cerebral atrophy
Brain weight in normal range though
pallor in substanstia nigra - midbrain and The locus coeruleus
where are the substanstia nigra and The locus coeruleus
what do they produce
substanstia nigra - mid brain and doapmine
midbrain and The locus coeruleus - pons and norephedrine
what are Lewy bodies made of
alpha synuclein
how dO LB differ from pick body
LB have central core and halo
Picks don’t
Pick made of Tau
another name for punch drunk syndrome
dementia pugilistica
coined by Millspaugh
who was punch drunk syndome seen in
and symptoms
NFL players
boxers
neuro trauma
slurred speech, impaired hearing, gait ataxis, cognitive dcline, behaviour change, impulse control , irritable
what type of condition is punch drunk syndrome
tauopathy
affect cortical slucus
perivascualr distrubition
