S12: antiepileptics & neuropharmacology Flashcards
Define seizure
Transient occurrence of signs or symptoms due to abnormal electrical activity in the brain
Leads to a disturbance of consciousness, behaviour, emotion, motor function/sensation
Outline the most important excitatory and inhibitory neurotransmitters
Glutamate + NMDA receptor: cation channel – lets in Na+ and Ca2+ and lets K+ out -depolarises membrane -more likely to fire action potential GABA and GABAa receptor: Cl- channel -hyperpolarise membrane -less likely to fire action potential
Explain the pathology of seizures
Seizure = clinical manifestation of abnormal and excessive excitation & synchronisation of a group of neurones within the brain
Loss of inhibitory signals OR too strong an excitatory one
Imbalance can happen in any point in the brain & local changes can lead to generalised effects
What causes an imbalance in signals in a seizure?
Genetic differences in brain chemistry/receptor structure = genetic epilepsy syndromes
By exogenous activation of receptors = drugs
Acquired changes in brain chemistry = drug withdrawal, metabolic changes
Damage to any of these networks = strokes, tumours
Outline the symptoms and signs of seizures
Generalised seizures: loss of consciousness often with changes in muscle tone, tongue biting
Tonic-clonic seizures: initial hypertonic phase, followed by rapid clonus (shaking/jerking) of the limbs
Post-ictal period present (can last minutes up to hours)
Often an aura prior to seizure
May be more varied or subtle depending on type of seizure
Define epilepsy
Tendency toward recurrent seizures unprovoked by a systemic/neurological insult
Describe the diagnosis of an epilepsy syndrome
At least two unprovoked seizures occurring more than 24 hours apart
One unprovoked seizure & a probability of further seizures similar to the general recurrence risk after two unprovoked seizures
List different stimuli that can bring on seizures
Photogenic Musicogenic Thinking Eating Hot water immersion Reading Orgasm Movement
Compare generalised seizures and focal seizures
Generalised seizures: originate at some point within and rapidly engage both hemispheres
Focal seizures: originate within networks limited to one hemisphere, may be discretely localised or more widely distributed
Describe provoked seizures
Seizure as a result of another medical condition
Examples include:
-drug use or withdrawal
-alcohol withdrawal
-head trauma & intracranial bleeding
-metabolic disturbances
Key is to treat both the seizure & underlying condition
List different diagnoses of seizures
Syncopal episodes
Cardiac issues (reflex anoxic seizures, arrythmias)
Movement disorders (Parkinson’s, Huntington’s)
TIAs
Migraines
Non-epileptic attack disorders
Describe the initial management of a seizure
A to E assessment
Look at a clock/start a timer (majority will self terminate without the use of drugs, wait 5 minutes)
Get some help
Define status epilepticus
A seizure (of any variety) lasting 5 minutes or more, or multiple seizures without a complete recovery between them Medical emergency
Outline the pharmacological treatment for status epilepticus
0-5 minutes: full dose benzodiazepine
0-15 minutes: 2nd full dose benzodiazepine
15-45 minutes: 2nd line anti-epileptic = phenytoin, levetiracetam (consider IV thiamine if alcohol use)
45+ minutes: thiopentone/anaesthesia (with support)
Describe benzodiazepines
GABAa agonists
Increased Cl- conductance = more negative resting potential, less likely to fire
Work best when membrane positive (in seizures), no firing neurones = no more seizure
Be aware: addiction, cardiovascular collapse & airway issues
Other indications: anxiolytics, sleep aids & alcohol withdrawal
List benzodiazepine options for status epilepticus
Intravenous lorazepam
Diazepam rectally
Buccal/intranasal midazolam
Describe investigations for epilepsy
Electroencephalography:
- record of electrical pattern of activity in brain
- can be very useful, especially if an attack is caught whilst being recorded
- many people without epilepsy have an abnormal EEG
Describe the role of imaging for epilepsy
MRI is the imaging of choice
May detect vascular or structural abnormalities that can account for epilepsy
Generally not required when there is a degree of confidence that there is a generalised epilepsy syndrome
List types of anti-epileptic drugs
Carbamazepine Phenytoin Valproate Lamotrigine Levetiracetam Benzodiazepines for seizure termination
What is SUDEP?
Sudden unexplained death in epilepsy
More frequent in people with poor seizure control
Describe sodium channel blockade (in AEDs)
Blocking of Na+ channels in central neurones
Slows recovery of neurones from inactive to closed state
Reduces neuronal transmission
Describe carbamazepine
Sodium channel blocker
Other indications: bipolar & sometimes chronic pain
Side effects: suicidal thoughts, joint pain & bone marrow failure
Describe phenytoin
Sodium channel blocker
Exhibits zero order kinetics
Side effects: bone marrow suppression, hypotension & arrythmias (IV use)
Describe sodium valproate
A mix of GABAa effects & sodium channel blockade
Specific side effects: liver failure, pancreatitis & lethargy
Describe lamotrigine
Primarily a sodium channel blocker, may also affect calcium channels
Good for focal epilepsy
Used often when valproate contraindicated in generalised epilepsy
Describe levetiracetam
Synaptic vesicle glycoprotein binder – stops the release of neurotransmitters into synapse and reduces neuronal activity
Option for focal seizures and generalised seizures
Safe in pregnancy
List side effects of anti-epileptic drugs
Tiredness/drowsiness
Nausea and vomiting
Mood changes and suicidal ideation
Osteoporosis
Rashes, including steven johnson syndrome; most likely in carbamazepine or phenytoin
Many cause anaemia, thrombocytopenia or bone marrow failure
Describe common DDIs of AEDs
Patients on AEDs and warfarin require close monitoring
Patients should not consume alcohol
Carbamazepine & phenytoin may decrease effectiveness of oral contraceptive pills & some antibiotics
Valproate can increase plasma concentration of other AEDs
Describe the link between AEDs and CYP enzymes
AEDs can be both inducers and inhibitors of CYP enzymes
Therefore, interact with a wide variety of drugs, including each other
Inducers: phenytoin, carbamazepine & barbiturates
Inhibitors: valproate
Describe the importance of family planning when female is on an AED
Some risk of congenital malformations with all AEDs
Valproate should not be prescribed to any woman of childbearing age unless they meet the conditions of a pregnancy prevention programme
Lamotrigine and levetiracetam are the safest
Describe epilepsy and driving
Need to ask all patients with seizures about driving
Temporarily lose license and needed to be seizure free for one year before reapplying
Patients responsibility to inform DVLA
Outline the basic classification of seizures
Focal onset seizures:
1) Aware – motor, somatosensory/psychic symptoms, consciousness not impaired
2) Impaired awareness – consciousness affected and may be confused
Generalised onset seizures:
1) Tonic-clonic – jerking and shaking as muscles relax and contract
2) Myoclonic – muscle jerking
3) Absence – abrupt loss of awareness
4) Atonic – loss of muscle tone, often collapse
Describe the pathophysiology of Parkinson’s disease
Loss of dopaminergic neurones in substantia nigra results in reduced inhibition in neostriatum
Loss of inhibition in neostriatum allows increased production of acetylcholine
Chain of abnormal signalling leads to impaired mobility
List clinical features of Parkinson’s disease
Tremor Rigidity Bradykinesia Postural instability Non-motor manifestations: mood changes, hallucinations, pain, urinary symptoms & sweating
List drug classes used to treat Parkinson’s disease
Levodopa Levodopa with COMT inhibitor Dopamine receptor agonists MAOI type B inhibitors Anticholinergics Amantadine
Describe levodopa (L-DOPA)
Dopamine precursor which allows it to cross BBB, must be taken up by dopaminergic cells in the SN to be converted to dopamine -> fewer remaining cells results in less reliable effect
Used in combination with a peripheral dopa decarboxylase inhibitor – reduced dose required, reduced side effects & increased levodopa reaching brain
Describe levodopa pharmacokinetics
Oral administration
Absorbed by active transport (in competition with amino acids)
90% inactivated in intestinal wall
List side effects and contraindications of levodopa
Side effects: N&V, anorexia, hypotension, psychosis, tachycardia
Contraindications: melanoma, diabetes, psychotic disorder, suicidal tendencies
List DDIs of levodopa
Pyridoxine (vitamin B6) increases peripheral breakdown of levodopa
MAOIs risk hypertensive crisis
Many antipsychotic drugs block dopamine receptors & parkinsonism is a side effect
Describe COMT inhibitors
Always use with levodopa
Reduces peripheral breakdown of levodopa
Prolongs to motor response to levodopa
List examples of dopamine receptor agonists
Ropinirole
Amantadine
Rotigotine
Apomorphine – only for patients with severe motor fluctuations
List side effects and contraindications of dopamine receptor agonists
Side effects: impulse control disorder, sedation, confusion, hallucination, hypotension, seizures
Contraindications: epilepsy, gastric ulcer
Describe monoamine oxidase B inhibitors
Rasagaline, selegiline
Enhance dopamine
Prolong action of levodopa but can be used alone
Smooth out motor response
Describe anticholinergics
Orphenadrine, procyclidine
Minor role in treatment of PD – effectiveness won’t decrease as lose dopaminergic neurones
Side effects: confusion, drowsy, bradykinesia, anticholinergic symptoms
Contraindications: acute porphyrias, GI obstruction
Describe amantadine
Mainly effective for levodopa induced dyskinaesia
Few side effects: hallucinations, confusion
Describe clinical features of myasthenia gravis
Fluctuating, fatigable, weak skeletal muscle
- extraocular muscles
- bulbar involvement: dysphagia, dysphonia & dysarthria
- limb weakness: proximal symmetric
- respiratory muscle involvement
Outline the therapeutic management of myasthenia gravis
Acetylcholinesterase inhibitors Corticosteroids – decrease immune response Steroid sparing – azathioprine IV immunoglobulin Plasmapheresis
Describe acetylcholinesterase inhibitors
Pyridostigmine, neostigmine Enhance neuromuscular transmission Skeletal & smooth muscle Excess dose can cause depolarising block Muscarinic side effects – SSLUDGE
List the muscarinic side effects
Salivation Sweating Lacrimation Urinary incontinence Diarrhoea GI upset and hypermotility Emesis
Name 4 types of generalised seizures
Absence
Myoclonic
Tonic-clonic
Atonic
