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PHARMACOLOGY FRCA > CNS drugs > Flashcards

CNS drugs Flashcards

1
Q

what is epilepsy?

A

chronic disease either congential or acquired

susceptibility to episodic abnormal spontaneous electrical discharge in the brain result in seizures.

can be categorised into generalised epilepsy whereby both hemispheres are effected and result in tonic clonic seizures or absence seizures or myoclonic seizures.

OR partial epilepsy effecting only one part of the brain and depending on region various symptoms are experienced. e.g. temporal lobe - lip smacking. sometimes consciousness is preserved and sometimes not.

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2
Q

what is a seizure

A

an episode of abnromal excessive excitatory acitivity within the brain. this may be focal affecting one region of the brain or diffuse effecting the whole brain

leads to a number of symptoms
classically tonic clonic seizures but also absence seizures, myoclonus, partial seizures may be sensory, auditory etc.

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3
Q

what are the differentials of epilepsy?

A

syncope /vasovagal
migraine
pseudoseizures

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4
Q

how are anti-epileptics classified ?

A

by mechanism of action
stop excitation…
1. VG Na channel blocker - Phenytoin, valproate, carbemazepine, lamotrigine - bind and block channel to prevent AP spreading.
2. glutamate blockers - valproate, topimarate
3. Ca channel modulators - pregabalin, gabapentin
4. SV2A protein - levetiracitam - blocks NT release via this protein

promote inihibition..
5. GABA receptors - benzodiazepines , barbiturates - allosteric modulators, prolong frequency and duration of GABA opening respectively. hyperpolarisation
6.. Glutamic acid decarboxylase modulation (GAD) - gabapentin, pregabalin. increase activity of GAD which converts glutamate to GABA

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5
Q

what acts on GABA- A and GABA - B

A

GABA A - benzo, barbiturates
GABA B - Baclofen

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6
Q

what are the risks of anti-epileptics in pregnancy?

A

some are teratogenic - valproate in particular + carbamazepine and phenytoin

safest is lamotrigine

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7
Q

how do AEDs affect CYP450?

A

phenytoin, carbemazepine, barbiturate = inducer

valproate = inhibitor

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8
Q

management of status epilepticus?

A

A to E approach

turn on side to protect airway
or jaw thrust

100% O2 via non rebreathe

Check BP, HR etc - observations + cardiac monitoring. IV access and bloods.

D:
check BMs and temp
give benzo - buccal/PR diazepam / midazolam
0.1mg/kg lorazepam IV - repeat after 10 mins
phenytoin infusion - 20mg/kg
GA and intubation - thiopentone
ITU admission

E:
look for cause - LP, CT head, thiamine, start on aciclovir, ceftriaxone etc

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9
Q

pre-op considerations in someone with epilepsy

A

pre -op HX
- type of seizures
- how long for , how often , i.e. how well managed
- medications and side effects of these

plan:
* continue meds until op
* could consider regional
* consider meds that dont alter seizure threshold e..g avoid ketamine, etomidate and enflurane.
* propofol and thio are safe
* aim for normocapnia, good MAP, avoid hypoxia - all reduce risk of seizure.

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10
Q

describe the GABA receptor?

A

GABA A
pentameric ligand gated ion channel receptor
spans plasma membrane , chloride channel.
subunits - 2a, 2b, g

GABA B
GPCR Gi- found pre and post synapse.
increases K+ conductance when stimulated

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11
Q

tell me about gabapentin

A

Gabapentin is an anti-epileptic medication and now more commonly used for neuropathic pain e.g. fibromyalgia, diabetic neuropathy, disc herniation

it has a number of mechanisms
* although it resembles GABA it is not a GABA agonist
* Ca channel modulator - reduces calcium entry and NT release such as substance P and glutamate (hence role in pain)
* GAD modulator - promoting GABA production

unfortunately a number of side effects
commonly nausea and weight gain

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12
Q

how do benzodiazepines work?

A

bind to the benzodiazapine receptors BZ1 and BZ2 which are closely linked to GABA and when bound to this the complex acts as a positive modulator of GABA.
increase the frequency of GABA channel opening hence more chloride conductance and hyperpolarisation.

Bz1 - mostly in spinal cord and cerebellum - anxiolysis
bz2 - mostly in spinal cord, cortex and hippocampus - sedative, anticonvulant

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13
Q

describe the general structure of benzos

A

aromatic lipophilic amines
2 benzene rings
1 diazepine ring (7 member ring structure with 2N and 5C)

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14
Q

what are the uses of benzodiazepines?

A

epilepsy
pre med
anxiolysis
muscle spasm
sedation

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15
Q

in what ways do benzos demonstrate tolerance/ dependance?

A

dependance can quickly develop within weeks of regular use
can lead to withdrawal symptoms - anxiety, tremor, poor sleep, seizures, muscle cramps. can kill.

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16
Q

which patient groups should care be taken when prescribing benzos?

A

elderly - risk of delirium, drowsiness and accumulation of metabolites

pregnancy - can cross BBB risk of hypotonia and resp distress in fetus

breast feeding - excreted in breast milk can cause resp depression in baby

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17
Q

how can benzos be categoried?

A

into short, medium and long acting

short = midazolam
medium = lorazepam
long = diazepam, chlordiazepoxide

18
Q

what is flumezanil?

A

competitive antagonist of BZD site on GABA receptor
used in treatment of benzodiazepine overdose

its half life (1hr) is often shorter than benzo and sometimes repeated bolus (0.2mg) or an infusion is needed. max 2mg

care should be taken as risk of precipitating seizures, withdrawal - shouldnt be used in mixed OD e.g. TCA or in those with epilepsy.

19
Q

what are the routes for midazolam administration?

A

IV
buccal
oral
IM
intranasal

20
Q

describe the molecular strucutre of midazolam

A

benzodiazepine and therefor an aromatic lipophilic amine
has 2 benzene rings and 1 diazepine ring

exhibits tautomerism - at low pH below its pKA (6.5) - it has an open structure and water soluble. at pH above pKa, it closes and becomes lipid soluble.

21
Q

how does the oral and buccal dose of midazolam compare?

A

oral = undergoes 1st pass metabolism
buccal avoids this

hence oral dose is higher to account for this.

22
Q

why is midazolam favoured in anaesthesia?

A

short half life
less likely to cause delirium and sedation after operation.

23
Q

how is benzodiazepine OD managed?

A

A to E
supportive - main problem is resp depression
flumezanil

24
Q

tell me about sodium valproate

A

anti epileptic agent
works via a number of mechanisms including VG Na channel blockage, GAD modulation, NMDA blockade.

used in epilepsy and trigeminal neuralgia and also as a mood stabilser

IV or oral

unfortunately a number of side effects
- VALPROATE = vomitting, alopecia, liver toxicity, pancretitis, retain fat, oedema, appeitite increase, tremor, enzyme inhibitor

25
Q

tell me about phenytoin

A

anti-epileptic and also class Ib anti-arrhythmic agent

used in status epilepticus and treatment of arrhythmias e.g. after TCA or digoxin toxicity

works via inhibiting VG Na channels.

a number of side effects unfortunately
* idiosyncratic - gum hyperplasia, hirsutism, acne, SLE, perpheral neuropathy
* conc dependant - heart block / hypotension, headaches, confusion, tremor, N&V
* teratogenic

pharmacokinetics
-exhibits 0 order kinetics when just above therapeutic range and therefore needs monitoirng
narrow therapeutic index
- CYP450 inducer

26
Q

what is depression

A

a mental health illness
thought to be due to an imbalance of NT within the brain
predominately a deficiency in NA, serotonin or downregulation of their receptors.

27
Q

how do anti-depressants work?

A

depression is thought to be due to reduction in serotonergic, dopamineric and NA pathways within CNS

anti-depressants work by targetting these to increase activity.

there are 4 main classes of drugs
* Selective serotonin reuptake inhibitors (SSRI) - fluoextine and sertraline
* serotonin- NA - reuptake inhibitors (SNRIs) - duloxetine and venlafaxine
* Tricyclic antidepressants - amitryptilline
* Monoamine oxidase inhibitors - phenelzine, moclobimide

28
Q

tell me about SSRIs

A

selective serotonin reuptake inhibitors
block reuptake of serotonin and hence increase serotonin levels in synapse to overcome the deficiency seen in depression

include sertraline and fluoextine
1st line in anxiety and depression

main side effects include - irritability, GI upset, nausea, anxiety at first.
caution for serotonin syndrome, long QTc
can get discontinuation syndrome if stopped abruptly - diarrhoea, anxiety, nausea

but overall good side effect profile

29
Q

tell me about the SNRIs…

A

serotonin - NA - reuptake inhibitors
venlafexine, duloxetine

have a role in depression and chronic pain

block both reuptake - helps increase levels - helps deficiency seen in depression

same side effect profile as SSRI
but now also HTN due to NA.

30
Q

tell me about the TCA..

A

tricyclic antidressants include amitripyltipine
often used in chronic neuropathic pain.
their use in depression mostly been replaced with newer safer agents.

they block reuptake of NA and 5HT3
also anti-muscarnic, antihistaminic and anti a1 adrenerfic

worse side effect profile as less specific
- reduce seizure threshold
- anticholinergic symptoms - dry mouth, tachycardia, blured vision, constipation
- prolonged QTc

31
Q

tell me about TCA overdose?

A

TCA have a narrow therapeutic window and are toxic in overdose

in particular they prolong QTc and reduce seizure threshold.

Overdose should be managed with A to E approach
manage seizures
alkalinisation of blood improves protein binding - sodium bicarb if metabolic acidosis

32
Q

what are the implications of someone on TCA in anaesthesia?

A

continue as normal
be aware can increase MAC

avoid drugs that promote NA release - ketamine, ephedrine

33
Q

what are the signs and symptoms of tricyclic OD?

A

symptoms of anti-cholinergic and sympathetic e.g. dry mouth, constipation, tachycardia, blurred vision

long QTc

metabolic acidosis

seizures

34
Q

what are monoamine oxidase inhibitors?

A

monoamine oxidase is an enzyme responsible for the breakdown of NA and serotonin (MAO-A)
it is located on mitochondrial membrane

by inhibiting this enzyme, levels of NA and 5HT3 can be increased to help treat depression.
also used in OCD and chronic pain, migraines.

e.g. moclobimide and phenelzine

rarely used due to interactions with tyramine containing foods (cheese, chocolate) and side effect profile e.g. HTN crisis

other side effects include weight gain and erectile dysfunction. also risk of serotonin syndrome.

35
Q

which drugs should be avoided with MAO-i?

A

anything increasing NA/ 5HT3
ephedrine, ketamine, amphetamines, cocaine, tramadol, pethidine, TCA

risk of HTN crisis and serotonin crisis

36
Q

what interactions between antidepressants and anaesthetic agents do you know?

A

a lot work by increasing NA and serotonin
therefore any anaesthetic agents doing similar will put them at risk of serotonin syndrome or HTN crisis

e.g.
pethidine and tramadol - increase NA and 5HT3
ephedrine - increases NA
ketamine - activates sympathetic NS hence NA
pancuronium - also increases NA

37
Q

what is serotonin syndrome?

A

Adverse drug reaction which is potentially life threatening due to increased levels of 5HT3

features include -
CNS: agitation, confusion, seizures
MSK: rigitdity, hyperreflexia and clonus, rhabdomyolyiss
CVS : tachycardia, hypotenison
autonomic - dilated pupils, hyperthermia, sweating

caused by 2 or more serotonergic drugs e.g. SSRI, SNRIs, cocaine, MDMA

38
Q

tell me about lithium

A

group 1 metal from period table
used for depression, bipolar
works via mimicking Na hence reduces excitability

unfortunately has a narrow therapeutic index with many side effects and thus needs monitoring.
common - tremor, D+V, weight gain
less common - seizures, haemolysis, bradycardia / AV block. nephrogenic diabetes insipidus (antagonises ADH), hypothyroidism.

in terms of anaesthesia - reduces MAC and prolongs NMBA

39
Q

how can neuroleptic malignant syndrome and serotonin syndrome be differentiated?

A

serotonin syndrome - from too much 5HT3
neuroleptic malginant syndrome - from dopamine receptor blockade hence assocaited with anti-psychotics

both cause - hyperthermia, muscle rigidity, altered mental state.

however serotonin is acute in onset causes hyperflexia and tremor. dilated pupils.
NMS is more gradual and causes hyporeflexia and led pipe rigidity. pupils are not usually dilated

40
Q

how do antipsychotics work?

A

thought to be due to too much dopamine
hence work via D2 receptor antagonism

e.g. schizophrenia and delirium

2 groups
first gen = typical = haloperidol, chlorpromazine
second gen = atypical = clozapine, rispiridone, quietiapine

41
Q

what are the main side effects of antipsychotics?

A

D2 antagonism can result in extrapyramidol effects - more common with first generation = tremor, bradykinesia, rigidity, akinesia, occulogyric crisis , tarditive dyskinesia

also results in more prolactin (as normally dopamine inhibits prolactin) - hence galactorrhoea and infertility

clozapine - important side effect = agranulocytosis
atypicals commonly cause weight gain

42
Q

what is occulogyric crisis?

A

types of extrapyramidal side effects

occulogyric crisis = acute involuntary dystonia of eyes - fixed upwards gaze. may also have other dystonias e.g. torticolis

cuased by anti-psychotics or acute withdrawal or dopamine agonists used in parkinsons

can be treated with anti-cholinergics e.g. procyclidine

PHARMACOLOGY FRCA (16 decks)

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