L8 - L15 Flashcards
Modified Release Capsules
- Madopar
- useful in PD with fluctuations in levodopa plasma concentrations. the slow release will give a steady plasma level
sodium valproate capsules (Episenta® epilepsy):
- capsule contains prolonged-release granules
- granules coated with an indigestible ethyl cellulose shell
Bipolar Disorder
- BP1 and 2
- cyclothymia
BP1 - manic episodes & significant depression
BP2 - extreme depression and hypomania (less severe form of mania)
Cyclothymia - similar to BPD but lower extremes & less swings
Lithium Treatment
- calms manic patients
- modulates GABA , glutamate , and interferes with cAMP
- S/E : thirst , tremor , confusion
Major Depressive Disorder
- key symptoms : persistent sadness, loss of pleasure, fatigue
associated symptoms : disturbed sleep, poor concentration, low self confidence, suicidal , agitation, guilt
MDD must have:
- symptoms present for 2 weeks at significant level
<4 - not depressed
4 - mild depression
5-6 - moderate
>7 - severe
Depression Monoamine Hypothesis
depression results from deficient monoamine transmission
- treated with monoamine oxidase inhibitors.
- depression comes from low levels of amines (NA , 5-HT , DA)
Problems : drugs act fast (hours) but takes weeks or months to see change
Neuromodulation
- Volume Transmission
- synaptic transmission fast & precise e.g. glutamate
Neuron has long axons, releasing at different places. = slow transmission
- G-coupled protein receptors
- transports monooamines
Noradrenergic - locus coeruleus
Dopaminergic - ventral tegmental area + SN
Serotonergic - raphe nucleus
Depression Treatments
1st CBT - interpersonal therapy, meditation
2nd Antidepressants - SSRI’s, SNRI’s, MAOI’s , TCA’s
- sertraline 50mg
- mirtazapine (causes sedation for patients who have insomnia)
3rd Electroconvulsive - shock therapy + vagus nerve stimulation
Antidepressants
- SSRI’s , MAOI’s , TCA’s
SSRI’s
- selective serotonin reuptake inhibitors
- sertraline (depression) Fluoxetine (BDD)
-MAOI’s - inhibit monoamine oxidase to allow amine build up (5-HT, D, NA)
-TCA’s inhibit presynaptic a2 receptors allowing NA build up
-SSRI’s, SNRI’s & TCA’s block these amine reuptake molecules to stop amine degradation
SSRI’s Overview
-S/E
-Contraindications
MOA : selectively bind to SERT in the presynapse
- allowing serotonin build up in synaptic cleft
- improve mood and motivation
S/E : bleeding risk , ED , nausea , suicide risk , serotonin syndrome
- citalopram causes QT prolongation
TCA’s
- amitryptaline , clomipramine
similar efficacy to SSRI’s, but more S/E
- used for nerve pain and depression
- TCA’s block the reuptake of monoamines to inc. their transmission
- TCA’s block presynaptic a2 receptors to further increase NA
- this stops ACh release and stimulates Na
S/E : antimuscarinic effects (dry mouth, blurriness) , cardiotoxicity, weight gain, overdose
Monoamine Oxidase Inhibitors
- block monoamine oxidase
- tranylcypromine , phenelzine
block the enzyme that breaks down important monoamines (NA, 5-HT, D)
- only given by specialist
- has hepatotoxicity
Food Reaction : tyramine enters nerve and displaces NA from vesicle causing large NA release & vasoconstriction
- leads to hypertensive headaches
- MAO releases tyramine and degrades in gut which can increase this
- so watch tyramine levels
Anxiety Overview
- irrational fear in the presence or absence of obvious stimuli that they cant get rid of
Pathology
- inc. adrenaline acts on organs
- Limbic System, altered sensitivity of GABA
- SoB , choking , palpitations , tremors , dry mouth , nausea , specific phobia
Generalised Anxiety Disorder
- Diagnosing
GAD-7 & DSM5 : used to assess severity
- persistent anxiety and uncontrollable worry for at least 6 months
Treating Anxiety
- Benzodiazepines
- only use for short term
- diazepam, lorazepam, midazolam
positive allosteric GABAa receptor modulator.
- inc. the opening of GABAa channels
- there is a specific mutation in a2 leading to lasting effect of BDZ’s
S/E : ED , dependence , interactions
Treating Anxiety
- SSRI’s
- 5-HT drug targets
5-HT1a : anxiety, alcoholism, sexual funct
5-HT1c : anxiety , migraine pain
5-HT1d : migraine pain
5-HT2 - anxiety , depression , schizo neg symptoms
5-HT3 : migraine , emesis , schizo
5-HT4 : anxiety and schizo
- no tolerance buildup
- used in depression and panic disorder too
- temp. worsening of symptoms and effects in 4-6 weeks
SSRI’s action
- Buspirone 5-HT1a agonist
SSRI’s dont cause weight gain
- safe in overdose
Buspirone - 5-HT1a agonist
- helps anxeity , alcoholism
- treats GAD
S/E - nausea and headache, ED
Clozapine MOA
- D4 and 5-HT2a
blocks 5-HT2a & 5-HT2c receptors
- along with D4
- 5-HT blockade regulates dopamine release in brain helping positive & negative symptoms
- strong affinity to block D4 in prefrontal cortex. reducing dopamine to control symptoms
S/E : major agranulocytosis - traffic light blood system checks every 18weeks inc. intervals
GAD Management
- Phases 1 to 4
- known presentations of GAD
- actively monitor & educate about GAD - diagnosed GAD not improving after education
- low intensity psychological intervention CBT - GAD with inadequate response to step 2 intervention
- high intensity psychological intervention or drugs (anxiolytics) - marked functional impairment & risk
- specialist treatment, complex drugs
SSRI’s - Development
- All SSRI’s have a halogen (F) on aromatic rings to stop hydroxylation
Citalopram - has racemic and S-only form escitalopram. is cardiotoxic
Fluoxetine - inhibits CYP450, affecting metabolism of other drugs. has lots of interactions
Paroxetine - one of the most potent SSRI
- conformationally restrained analogue of fluoxetine
Neurosis vs Psychosis
- insight , grasp of reality , personality , examples
Neurosis
- insight , grasp of reality , no delusions , resemble normal personality
- non invasive treatment
- anxiety , mild depression , obsession
Psychosis
- no insight or grasp of reality.
- hallucinations
- invasive treatment may be necessary
- schizophrenia , mania
Benzodiazepines BDZ’s
- Compliance
- dependence after 4-6 weeks of treatment
treats psychosis , epilepsy , psychotic symptoms
- dependency warning - decrease dose 1/8th every 2 weeks
- positive allosteric GABAa NT promoter
SSRI’s Compliance
- suicide risk so small supply given
- use full dose for 4-6month after symptoms have gone to prevent relapse
-non-compliance is common when patient mood has improved
- withdrawal is over 2-4 weeks
Extended Release Capsules
- Diffusion/Erosion : Methylphenidate (equasym XL)
- no impact on food intake10
- some beads have no coat. 30% rapid release. this is erosion step.
- 70% have coating making them sustained release.
- capsule broken down over time , eroding away, releasing coated granules over 8hrs
- diffusion and erosion step
Transdermal Administration
- Patches
- methylphenidate (daytrana)
- buprenorphine (butrans)
Matrix Patch - methylphenidate Daytrana
- apply to hip 2hrs before effect is needed
- remove 9hrs after application
WARNINGS: cardiotoxic. very dangerous in children with heart problems
- long term growth suppression and weight over 3 years
Antipsychotic + Antidepressant Safety
- Antidepressant - serotonin syndrome can cause tremors and tachycardia , neuronal hyperactivity
Antipsychotic
- metabolic syndrome & thromboembolism
- QT elongation
- clozapine FGA for agranulocytosis (check bloods first)
- titrate from 25mg daily up to 900mg max
Requirements : monitoring quarterly- must check neutrophil >2 x 10^9/L
- 0-18 weeks = weekly bloods
- 18-36 weeks = fortnightly bloods
- after 36 = monthly blooods
monitor every 3 months : ECG, HR, BP, temp, LFT’s
BDZ’s Safety + Lithium
Benzodiazepines
- withdrawal : convert to diazepam dose
- Discontinuation : reduce by 1/8 - 1/6 of daily dose every fortnight for 6months
Lithium
treats BPD & recurring depression
- teratogenic
- must assess renal , cardiac , thyroid and metabolic function before starting
Acute Psychosis
- psychiatric emergency
- person loses contact with reality
3 stages - prodromal , acute , recovery
- symptoms : delusions, cognitive impairment
Causes : neurological condition (dementia, Alzheimer’s, PD)
- brain injury , S/E from meds
- alcohol withdrawal / substance misuse
Treatment : antipsychotic + psychological
- reduces anxiety quickly but may take weeks to help psychotic symptoms
Mental Health Act 2003
- you can give medication to treat mental disorders to any patient without (or against) consent if it is for the patients wellbeing or others
Delirium Pathophysiology
- disruptions in higher cortical functioning in unrelated areas of the brain
- dopamine excess may contribute
can be caused by meds : anticholinergics , antiepileptics, opioids, steroids
- patient is disconnected from reality.
- hallucinations
- not acting normal
Delirium Symptoms
- causes distress, can come suddenly, often has physical cause
increased risk of mortality while delirious
- unsure where you are or what your doing
- unable to hold conversations
- very sleepy but awake at night
- moods change quickly and to extremes
- hear noises/voices and see things
Delirium Treatment
- Antipsychotics - Haloperidol
- Benzodiazepines
Haloperidol 0.5-1mg oral (max 2g/24hr)
- Haloperidol 0.5mg IM if oral not possible
- Rispiradone 250-500mcg oral (max 2g)
- reduce dose for frail
BZD’s if antipsychotics contraindicated
- Lorazepam 0.5mg-1g orally (max 2g/day)
- midazolam 2mg IM (max 6g/day)
Alcohol Withdrawal
- treat with BDZ
Diazepam every day change
- 20mg 6hrly
- 15mg 6hrly
- 10mg 6hrly
- 5mg 6hrly
- 5mg 12hrly
Schizophrenia Symptoms
- positive : added to normal behaviour
- negative : takes away from normal
- Cognitive : affects the mind
Positive Symptoms
- hallucinations , tremors , delusions ,
Negative Symptoms
- social withdrawal , sight/hearing/speech loss , lack motivation , ataxia
Cognitive Function
- long-term disability , disorganised thoughts
Schizophrenia Antipsychotic Treatment
- FGA’s (chlorpromazine)
- SGA’s (clozapine, olanzipine)
FGA’s - all act on dopaminergic receptors ONLY
- less impact on negative symptoms, NO effect on cognitive symptoms
- only for positive symptoms
- targets D2 (D2, 3, 4) for positive symptom reduction
SGA’s - act on dopaminergic and 5-HT2a
- less affinity for D2 family , more for D1
- works on negative symptoms too
Schizophrenia Treatment Guidelines
1st line : Atypical antipsychotics SGA’s
- amisulpride
- risperidone if they are aggressive
2nd line
- Treatment resistant Schizo
- Clozapine
- affinity for D1 + D2 , 5-HT2 to stop neurotransmitter release
BDZ Tolerance Building
- brain relies on BDZ’s for GABA function
BDZ’s are GABAa positive allosteric modulator, increasing frequency of GABA channel opening , increasing inhibitory neurotransmission
- causes sedation
- If BDZ’s are stopped suddenly, the brain wont go back to normal GABA function quickly.
- overpowered Glutamate concentration with cause hyper excitability in the brain
Schizophrenia Causes
- structural abnormalities that lead to functional abnormalities
(diagnosed in late teens or early 20s)
thinning of prefrontal + cerebral cortex
- this impairs working memory
grey matter loss in hippocampus & temporal pole
- this is a result of reduced synaptic processes
Smaller thalamus
- may be resulting from cell death
Schizophrenia Causes
- Genetic Cause
- chromosome translocation in 1 & 11 which inactivates DISC-1 gene
- DISC-1 is needed for key cellular processes in the brain
- Many genes associated with SZ are expressed during neurodevelopment.
Schizophrenia Dopamine Hypothesis
- some drugs that block D2 receptors reduce psychotic symptoms
Schizophrenia associated with hyperactive dopamine systems
- increases in dopamine at synapses can cause psychotic symptoms
-dopamine activity is decreased in corticol regions
- number of D1 receptors in PFC is reduced affecting cognitive symptoms
Schizophrenia Glutamate Hypothesis
- Decreased function of NMDA-type glutamate receptors may affect positive & cognitive symptoms of SZ
- Decreased function of NMDA-type glutamate receptors may affect positive & cognitive symptoms of SZ
Phencyclidine + Ketamine :
- blocks NMDA-type glutamate receptor causing psychotic symptoms
