CNS drugs Flashcards
what is epilepsy?
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.
what is a seizure
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.
what are the differentials of epilepsy?
syncope /vasovagal
migraine
pseudoseizures
how are anti-epileptics classified ?
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
what acts on GABA- A and GABA - B
GABA A - benzo, barbiturates
GABA B - Baclofen
what are the risks of anti-epileptics in pregnancy?
some are teratogenic - valproate in particular + carbamazepine and phenytoin
safest is lamotrigine
how do AEDs affect CYP450?
phenytoin, carbemazepine, barbiturate = inducer
valproate = inhibitor
management of status epilepticus?
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
pre-op considerations in someone with epilepsy
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.
describe the GABA receptor?
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
tell me about gabapentin
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
how do benzodiazepines work?
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
describe the general structure of benzos
aromatic lipophilic amines
2 benzene rings
1 diazepine ring (7 member ring structure with 2N and 5C)
what are the uses of benzodiazepines?
epilepsy
pre med
anxiolysis
muscle spasm
sedation
in what ways do benzos demonstrate tolerance/ dependance?
dependance can quickly develop within weeks of regular use
can lead to withdrawal symptoms - anxiety, tremor, poor sleep, seizures, muscle cramps. can kill.
which patient groups should care be taken when prescribing benzos?
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
how can benzos be categoried?
into short, medium and long acting
short = midazolam
medium = lorazepam
long = diazepam, chlordiazepoxide
what is flumezanil?
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.
what are the routes for midazolam administration?
IV
buccal
oral
IM
intranasal
describe the molecular strucutre of midazolam
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.
how does the oral and buccal dose of midazolam compare?
oral = undergoes 1st pass metabolism
buccal avoids this
hence oral dose is higher to account for this.
why is midazolam favoured in anaesthesia?
short half life
less likely to cause delirium and sedation after operation.
how is benzodiazepine OD managed?
A to E
supportive - main problem is resp depression
flumezanil
tell me about sodium valproate
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
tell me about phenytoin
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
what is depression
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.
how do anti-depressants work?
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
tell me about SSRIs
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
tell me about the SNRIs…
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.
tell me about the TCA..
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
tell me about TCA overdose?
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
what are the implications of someone on TCA in anaesthesia?
continue as normal
be aware can increase MAC
avoid drugs that promote NA release - ketamine, ephedrine
what are the signs and symptoms of tricyclic OD?
symptoms of anti-cholinergic and sympathetic e.g. dry mouth, constipation, tachycardia, blurred vision
long QTc
metabolic acidosis
seizures
what are monoamine oxidase inhibitors?
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.
which drugs should be avoided with MAO-i?
anything increasing NA/ 5HT3
ephedrine, ketamine, amphetamines, cocaine, tramadol, pethidine, TCA
risk of HTN crisis and serotonin crisis
what interactions between antidepressants and anaesthetic agents do you know?
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
what is serotonin syndrome?
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
tell me about lithium
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
how can neuroleptic malignant syndrome and serotonin syndrome be differentiated?
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
how do antipsychotics work?
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
what are the main side effects of antipsychotics?
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
what is occulogyric crisis?
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
