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Clinical Pharmacology And Therapeutics > CNS > Flashcards

CNS Flashcards

1
Q

Define seizure

A

Manifestation of inappropriately raised cortical electrical activity

Power surge of neural activity in the brain

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2
Q

Define epileptic seizure

A

A transient occurrence of symptoms due to abnormal excessive or synchronous neuronal activity in the brain

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3
Q

Define epilepsy

A

A disorder of the brain characterised by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological and social consequences of this condition

Need to have had more than one seizure to have epilepsy

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4
Q

What are some reasons for having a single / first seizure

A

Head Injury
Alcohol withdrawal
Drugs
Metabolic disturbance
Stroke
Onset of epilepsy
Tumour
Infection
Diabetes complication

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5
Q

What is epileptogenesis

A

The process by which a brain network that was previously normal is functionally altered toward increased seizure suscpetibility, thus having an enhanced probability to generate spontaneous recurrent seizures

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6
Q

In what ways are epileptics brains more excitable

A

Structurally:
- tumours
- scars

Congenital
- channelopathies (genes for ion channels)
- abnormal neural networks

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7
Q

What are the 2 main types of seizures

A

Generalised - spread across whole cerebral cortex

Focal - exist in one hemisphere or part of one hemisphere

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8
Q

How can focal seizures be divided

A

Simple focal : consciousness spared. Usually in frontal or occipital lobe

Complex focal : consciousness affected. Usually in temporal lobe

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9
Q

How can generalised seizures be divided

A

Tonic clonic

Myoclonus

Absence

Consciousness always affected

Sometimes simple focal or complex focal can spread to other parts of the brain and manifest as generalised tonic clonic

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10
Q

What to expect with a simple focal seizure

A

Same as an epileptic aura

No consciousness impairment

Focal epileptic discharge

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11
Q

What are the 3As in terms of complex focal seizures

A

Aura: may be initially fully conscious
Altered consciousness: usually partially responsive
Automatisms:
- lip smacking
- teeth grinding
- fiddling with clothes and objects

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12
Q

What are some typical characteristics of a complex focal seizure

A

Wandering, pacing, circing

Absence common but typically not the sole feature

Typically the most bizarre seizure type

Longest in duration (several mins - 1 hr)

Variable disorientation afterwards, amnesia for the event

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13
Q

What are the classic symptoms of a frontal lobe seizure

A

Thrashing of the arms,
Losing control of the bladder or bowels

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14
Q

Classic symptoms of a temporal lobe seizure

A

Plucking at clothes
Smacking lips

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15
Q

Classic symptoms of a occipital lobe seizure

A

Flashes of light
Brief loss of vision

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16
Q

Classic symptoms of a parietal lobe seizure

A

Tinging / warm feeling down one side of the body

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17
Q

Features of a generalised seizure

A

Very brief (1sec)
Shock like
Muscle contraction
Usually bilateral
Falls
Full immediate recovery
Loss of consciousness too brief to be appreciated

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18
Q

Features of absence seizures

A

Brief (<10 sec)
Abrupt loss of consciousness
Vacant stare
Speech arrest
Usually no motor signs
Tone unaffected
Full immediate recovery
Unaware of episode
Often missed / misinterpreted as daydreaming

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19
Q

Features of a generalised tonic clonic seizure

A

Possible aura
Ictus
Clonic phase:
- jerking limbs
- reducing frequency
- intermittent / suspended breathing
- tongue bitten
- urinary incontinence

Afterwards: drowsy, disoriented, out of sorts

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20
Q

What do anti-epileptic drugs target

A

Sodium channels
Block the channels when there is excess activity
They prolong the inactivated state of the channel
Block increases with repetitive activation
Reduces burst firing

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21
Q

What are the 3 main anti epileptic drugs that target sodium channels

A

Carbamazepine and Lamotrigine - can also block pre synaptic calcium channels
Phenytoin

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22
Q

When is carbamazepine used

A

In focal and generalised tonic clonic seizures
Not used in absence of myoclonic seizures as can exacerbate these
Slow release preparation to avoid plasma peaks in drug of narrow therapeutic range

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23
Q

When is carbamazepine contraindicated

A

In patients with acute porphyria’s, unplaced AV conduction abnormalities or history of bone marrow depression

Use with caution in patients with cardiac disease or angle closure glaucoma

Increased risk of major congenital malformations in the fetus if taken during pregnancy in 1st trimester

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24
Q

When is Lamotrigine used

A

Focal and generalised tonic clonic seizures in adults and children

Can cause skin rashes which are occasionally severe

Safer to take in pregnancy than carbamazepine

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25
Q

When is Lamotrigine contraindicated

A

In patients with myoclonic seizures or Parkinson’s disease as can exacerbate these

Use with caution in patients with brugada syndrome (heart block)

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26
Q

When is phenytoin used

A

Focal and generalised tonic clonic seizures

Also used IV to treat status epilepticus

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27
Q

When is phenytoin contraindicated

A

In patients with acute porphyria’s
IV use contraindicated in patients with heart block, sinus bradycardia and stokes adams syndrome

Use with caution in patients with absence and myoclonic seizures as can exacerbate these

Cross sensitivity with carbamazepine

Can cause antiepileptic hypersensitivity syndrome

Increased risk of congenital malformations in the foetus if taken during pregnancy

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28
Q

Which other anti epileptic drugs promote inhibition

A

Benzodiazepines such as lorazepam, midazolam, clonazepam and clobazam
- enhance CI- current as GABA receptors

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29
Q

When are midazolam and lorazepam used

A

In emergency situations such as status epilepticus or febrile convulsions

Buccal administration for midazolam

Slow IV administration for lorazepam

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30
Q

When are midazolam and lorazepam contraindicated

A

Similar to benzodiazepines
- avoid abrupt withdrawal of drug
Avoid in patients with resp disease
Avoid in patients with history of alcohol or substance misuse

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31
Q

When is clonazepam used

A

Suitable for all forms of epilepsy in adults and children

NOT the same as clobazam which is an adjunctive therapy in epilepsy.

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32
Q

When is clonazepam contraindicated

A

Similar to other benzodiazepines
- avoid abrupt withdrawal of drug
- avoid in patients with resp disease
- avoid in patients with history of alcohol or substance misuse
- avoid clonazepam in patients with acute porphyria

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33
Q

What is valproate

A

An inhibitor of GABA transaminase - ultimately reducing GABA metabolism and increasing GABAergic neurotransmission

Not widely understood - complex pharmacology

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34
Q

When is sodium valproate / valproic acid used

A

Suitable for all forms of epilepsy in children and adults

  • very effective
  • good side effect profile
  • avoid in hepatic impairment
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35
Q

When is sodium valproate / valproic acid contraindicated

A

Not used in female patients of childbearing age unless the conditions of the pregnancy prevention programme are met and there is no suitable alternative medication

Highly teratogenic 30-40% risk of neurodevelopmental disorders and 10% risk of major congenital malformation

Also not safe to take while breast feeding

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36
Q

Which anti-epileptic drugs are enzyme inducers and what effects does this have

A

Carbamazepine, phenytoin and topiramate

They increase the metabolism of oestrogen and progesterone so can make contraceptives less effective by reducing hormone levels up to 50%

Progesterone only contraception is not recommended and patients taking combined pill should be counselled about dosage
Barrier methods also recommended in addition

37
Q

How can enzyme inducers have affects in ways other than contraceptives

A

Can interfere with the metabolism of some chemotherapeutic agents resulting in poorer outcomes

Can reduce bone health through their effects on vit D metabolism, leading to reduced bone mineral density and an increased risk of osteoporosis and bone fracture

Can also increase the metabolism of several antidepressants and antipsychotic drugs leading to less effective treatment

38
Q

How to counsel a patient on anti epileptics about suicidal thoughts

A

Increased risk with any AED of suicidal thoughts and behaviour

Patients and carers should be advised to seek medical advice if any mood changes, distressing thoughts or feelings about suicide or self harming tendency

Also should be advised not to stop or switch antiepileptic treatment and to seek advice from healthcare professional if concerned

39
Q

What are the core symptoms of clinical depression

A

2 weeks of low mood
Loss of interest or pleasure in everything plus 3 or 4 of:
- change in sleep
- change in appetite
- low energy
- poor concentration
- restlessness
- low self worth
- suicidal thoughts / ideas
- concern over impending death

40
Q

What are 2 recommended screening questions for depression

A
  1. During the last month have you often been bothered by feeling down, depressed or hopeless
  2. During the last month have you often been bothered by having little interest or pleasure in doing things
41
Q

What are the 4 main strands of evidence underpinning investigations into the causes and treatment of depression

A
  1. Anatomical changes in the brain systems involved in mood
  2. Hyperactivity in the HPA system
  3. Neurotrophic hypothesis
  4. Monoamine hypothesis; based on actions of antidepressant drugs
42
Q

How do anatomical changes cause depression

A

Reduced volume of thalamus, amygdala and hippocampus result in patients suffering from severe depression

43
Q

How do changes to the HPA pathway cause depression

A

HPA pathway promotes the release of cortisol from the adrenal gland
In depression levels of cortisol are elevated and the size and activity of the pituitary gland and adrenal glands are elevated

44
Q

How do antidepressants act on the HPA pathway

A

Enhance negative feedback and decrease the HPA axis hyperactivity

45
Q

What is BDNF

A

Brain derived neurotrophic factor
Is responsible for regulating neurogenesis, development, dendritic growth, survival and maturation

46
Q

What is the neurotrophic hypothesis of depression

A

Depression is associated with reduced brain BDNF levels

Antidepressants can increase BDNF levels

47
Q

What is the monoamine hypothesis

A

Depression is the result of reduced monoamine signalling
- the antihypertensive drug reserpine caused depression in some patients. Reserpine depletes NA and 5-HT vesicles

CSF in suicidal depressed patients contains reduced levels of 5-HT; implies reduced levels of 5-HT in the brain
Most antidepressants elevate 5-HT and / or NA signalling

48
Q

Mechanism and examples of SSRIs

A

Fluoxetine and sertraline
Is a serotonin (5-HT) selective reuptake inhibitor

49
Q

Examples of and mechanism of SNRIs

A

Duloxetine and venlafaxine
Serotonin-noradrenaline reuptake inhibitors

50
Q

Examples and mechanism of tricyclic antidepressants

A

Lofepramine
Non selective reuptake inhibitors (5-HT and NA)

51
Q

Examples and mechanism of MAOIs

A

Moclobemide
Blocks breakdown of 5HT and NA

52
Q

Examples and mechanism of NASSAs

A

Mirtazepine
Selective receptor block that enhances NA and 5-HT signalling

53
Q

What are the first and second line antidepressant treatments

A

1st line = SSRI
2nd line = tricyclic

54
Q

Side effects of SSRIs

A

Generally mild and better than other classes
- GI disturbance: nausea, indigestion, diarrhoea or constipation
- psychiatric: sleep disorders, anxiety, agitation
- sexual: loss of libido, impotence

Increased risk of gastric bleeding
High likelihood of drug interactions

Most improve over time except sexual

55
Q

Describe the side effect profile of SNRIs

A

Similar mechanism of action and side effects to SSRIs

Venlafaxine reported to have a higher risk of death from overdose and should be avoided in patients at significant risk of suicide

56
Q

Describe the side effects of TCAs

A

Effects histamine H1 so can cause sedation and cholinergic (dry mouth, blurred vision)

Possible cardiovascular effects can be fatal in overdose

Lofepramine has the lowest risks in overdose

57
Q

MOA of NASSAs

A

Selectively block NA and 5-HT by MAO

Block a2 receptors
Block 5-HT2 and 5-HT3 receptors
This enhances signalling at certain NA and 5-HT synapses

58
Q

Side effects of NASSAs

A

Fewer sexual problems but can cause more drowsiness
Headaches, nausea, anxiety, postural hypotension, constipation, diarrhoea

Recommend to stop treatment if bipolar patient enters a manic episode

59
Q

Why are MAOIs only prescribed by mental health specialists

A

Because they have serious and fatal side effects including the cheese reaction which is an interaction with tyramine from certain foods that can lead to a hypertensive crisis

60
Q

What are the NICE recommendations for mild depression

A

Use non pharmacological interventions
If these are ineffective offer an SSRI

61
Q

What does NICE recommend for moderate to severe depression (or depression with a chronic health problem)

A

First use a generic SSRI as have a more favourable side effect profile and are safer in overdose

62
Q

What are the hypothesised causes of psychosis

A
  1. Dysfunctional development of the frontal cortex with early environmental factors important
  2. Over activity of subcortical dopamine neurones (affects D2 and D3 receptors)
  3. Cortical glutamate hypofunction and loss of GABA interneurones
63
Q

Describe the 2 dopamine receptor subtypes

A

D1 and D2
D1 subtype comprises D1 and D5 subunits
D2 subtype comprises D2, D3 and D4 subunits

It is receptors in the D2 subtype that are targeted by antipsychotics
All antipsychotics are D2 antagonists

64
Q

What are the positive symptoms of psychosis

A

Delusions
Hallucinations
Disorganised speech

65
Q

What are the negative symptoms of psychosis

A

Flat affect
Reduced speech
Lack of initiative

66
Q

What are the 1st generation antipsychotics

A

Typical antipsychotics (1950s and 60s)

67
Q

What are the 2nd generation antipsychotics

A

Atypical antipsychotics 1970s and 80s

68
Q

What are the 3rd generation antipsychotics

A

3rd generation atypical

69
Q

What is d2 antagonism

A

D2 antagonism in the Mesolimbic pathway is believed to be responsible for antipsychotic effect but this takes weeks to have an effect

The drugs block the D2, d3 or D4 subunit

70
Q

What side effects does D2 antagonism in other dopamine systems cause

A
  1. Nigrostriatal - extrapyramidal side effects
  2. Tuberoinfundibular- raised prolactin
  3. Mesolimbic - worsening cognitive function
71
Q

What are the extra pyramidal side effects that can be caused by D2 antagonism

A

Acute dystonia : neck or spine spasms or rigidity and oculogyric crisis

Pseudo-Parkinsonism: rigidity, tremor and Bradykinesia

Akathisia: inability to sit still, restlessness and agitation

Tardive dyskinesia: abnormal movement of the face, mouth or jaw, lip smacking, tongue protrusion, grimacing, bodily writhing

72
Q

What are some specific side effects of chlorpromazine

A

Sedation (H1 antagonism)
Weight gain (5HT2c antagonism)
Skin and eye effects (urticaria, photosensitivity, lens and corneal granulation)
Autonomic effects

73
Q

What autonomic side effects are caused by chlorpromazine

A

Muscarinic antagonism: atropine like- dry mouth, constipation, failure to ejaculate, urinary retention

Alpha adrenergic antagonism: miosis, cutaneous flushes, postural hypotension

74
Q

What are atypical antipsychotics

A

Effective against positive symptoms in the same way as typical

Partially effective against negative symptoms (unlike typical)

Minimal effect on cognitive deficit

Recommended in conjunction with CBT

75
Q

How do the pharmacodynamics vary between risperidone and olanzapine

A

Risperidone: D2 and 5HT2 antagonist

Olanzapine: weak D2 and 5-HT2 antagonist

76
Q

What are the side effects of atypical antipsychotics

A

Fewer Extrapyramidal side effects - limbic selective D2/D3 antagonism

Hyperprolactineamia

Weight gain due to 5-HT2c antagonism

There are additional side effects specific to individual drugs

77
Q

What is the order of what quetiapine blocks

A

H1 > a1 > 5-HT2 > a2 > D2

78
Q

When is clozapine used

A

In treatment resistant schizophrenia
- unsatisfactory clinical improvement following at least 2 different antipsychotic agents
- also used for patients with severe, untreatable neurological adverse reactions to other antipsychotics

79
Q

Why does clozapine have an unusual receptor pharmacology

A

High 5-HT2A and moderate D4 affinity but low D2 affinity

Very low risk of EPSE but constipation and salivation side effects (M1 and a1 antagonism)

Regular blood tests due to risk of agranulocytosis (consultant only prescribing)

80
Q

What is aripiprazole

A

3rd generation atypical antipsychotic

Partial agonist at D2 and 5-HT1A; 5-HT2A antagonist

EPSE similar to placebo but akathisia more common that expected

Common side effects include: insomnia, nausea, restlessness

81
Q

Outline 3 prescribing principles in antipsychotics

A
  1. Use the lowest possible dose - dose increase should only take place after 2 weeks of assessment, showing poor or no response
  2. Use of a single antipsychotic is recommended - except for short periods eg changing medication or in exceptional circumstances eg clozapine augmentation
    Increased risk of prolonged QTc and sudden death
  3. Response to drug treatment should be regularly assessed
82
Q

What causes weight gain with antipsychotics

A

Reduced metabolism
Increased appetite and endocrine effects
Increased leptin levels
Fluid retention

83
Q

Which drugs caused QT prolongation and what are the risks associated with this

A

Antipsychotic, antidepressants, antibiotics

Cause an increased risk of ventricular arrhythmias, syncope and sudden death syndrome

84
Q

What can you do if compliance to antipsychotics becomes an issue

A

Long acting injections
Sustained release formulation indicated for poor compliance

Injected into large muscle every 1-4 weeks (buttock, thigh, deltoid)

Same side effects as oral equivalent

85
Q

What supplements are recommended for people who are pregnant and on anti epileptics

A

Folic acid prior to conception and during pregnancy to reduce the chances of neural tube defects

86
Q

Are people on anti epileptic drugs for their whole life

A

No
If you have been seizure free for 2-4 years then the aim is to gradually withdraw therapy

87
Q

Which anti epileptic drug requires extensive drug monitoring

A

Phenytoin

88
Q

Does carbamazepine require extensive monitoring

A

No only phenytoin does as it demonstrates zero order pharmacokinetics

89
Q

If started on an AED are you on it for the rest of life

A

No the aim would be to withdraw therapy gradually after 2-4 years if seizure free

Clinical Pharmacology And Therapeutics (7 decks)

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