S12: antiepileptics & neuropharmacology

Question 1

Define seizure

Answer 1

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

Question 2

Outline the most important excitatory and inhibitory neurotransmitters

Answer 2

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

Question 3

Explain the pathology of seizures

Answer 3

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

Question 4

What causes an imbalance in signals in a seizure?

Answer 4

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

Question 5

Outline the symptoms and signs of seizures

Answer 5

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

Question 6

Define epilepsy

Answer 6

Tendency toward recurrent seizures unprovoked by a systemic/neurological insult

Question 7

Describe the diagnosis of an epilepsy syndrome

Answer 7

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

Question 8

List different stimuli that can bring on seizures

Answer 8

Photogenic 
Musicogenic 
Thinking
Eating
Hot water immersion 
Reading 
Orgasm 
Movement

Question 9

Compare generalised seizures and focal seizures

Answer 9

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

Question 10

Describe provoked seizures

Answer 10

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

Question 11

List different diagnoses of seizures

Answer 11

Syncopal episodes
Cardiac issues (reflex anoxic seizures, arrythmias)
Movement disorders (Parkinson’s, Huntington’s)
TIAs
Migraines
Non-epileptic attack disorders

Question 12

Describe the initial management of a seizure

Answer 12

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

Question 13

Define status epilepticus

Answer 13

A seizure (of any variety) lasting 5 minutes or more, or multiple seizures without a complete recovery between them 
Medical emergency

Question 14

Outline the pharmacological treatment for status epilepticus

Answer 14

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)

Question 15

Describe benzodiazepines

Answer 15

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

Question 16

List benzodiazepine options for status epilepticus

Answer 16

Intravenous lorazepam
Diazepam rectally
Buccal/intranasal midazolam

Question 17

Describe investigations for epilepsy

Answer 17

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

Question 18

Describe the role of imaging for epilepsy

Answer 18

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

Question 19

List types of anti-epileptic drugs

Answer 19

Carbamazepine 
Phenytoin 
Valproate 
Lamotrigine 
Levetiracetam 
Benzodiazepines for seizure termination

Question 20

What is SUDEP?

Answer 20

Sudden unexplained death in epilepsy

More frequent in people with poor seizure control

Question 21

Describe sodium channel blockade (in AEDs)

Answer 21

Blocking of Na+ channels in central neurones
Slows recovery of neurones from inactive to closed state
Reduces neuronal transmission

Question 22

Describe carbamazepine

Answer 22

Sodium channel blocker
Other indications: bipolar & sometimes chronic pain
Side effects: suicidal thoughts, joint pain & bone marrow failure

Question 23

Describe phenytoin

Answer 23

Sodium channel blocker
Exhibits zero order kinetics
Side effects: bone marrow suppression, hypotension & arrythmias (IV use)

Question 24

Describe sodium valproate

Answer 24

A mix of GABAa effects & sodium channel blockade

Specific side effects: liver failure, pancreatitis & lethargy

Question 25

Describe lamotrigine

Answer 25

Primarily a sodium channel blocker, may also affect calcium channels Good for focal epilepsy Used often when valproate contraindicated in generalised epilepsy

Question 26

Describe levetiracetam

Answer 26

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

Question 27

List side effects of anti-epileptic drugs

Answer 27

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

Question 28

Describe common DDIs of AEDs

Answer 28

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

Question 29

Describe the link between AEDs and CYP enzymes

Answer 29

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

Question 30

Describe the importance of family planning when female is on an AED

Answer 30

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

Question 31

Describe epilepsy and driving

Answer 31

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

Question 32

Outline the basic classification of seizures

Answer 32

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

Question 33

Describe the pathophysiology of Parkinson’s disease

Answer 33

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

Question 34

List clinical features of Parkinson’s disease

Answer 34

``` Tremor Rigidity Bradykinesia Postural instability Non-motor manifestations: mood changes, hallucinations, pain, urinary symptoms & sweating ```

Question 35

List drug classes used to treat Parkinson’s disease

Answer 35

``` Levodopa Levodopa with COMT inhibitor Dopamine receptor agonists MAOI type B inhibitors Anticholinergics Amantadine ```

Question 36

Describe levodopa (L-DOPA)

Answer 36

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

Question 37

Describe levodopa pharmacokinetics

Answer 37

Oral administration Absorbed by active transport (in competition with amino acids) 90% inactivated in intestinal wall

Question 38

List side effects and contraindications of levodopa

Answer 38

Side effects: N&V, anorexia, hypotension, psychosis, tachycardia Contraindications: melanoma, diabetes, psychotic disorder, suicidal tendencies

Question 39

List DDIs of levodopa

Answer 39

Pyridoxine (vitamin B6) increases peripheral breakdown of levodopa MAOIs risk hypertensive crisis Many antipsychotic drugs block dopamine receptors & parkinsonism is a side effect

Question 40

Describe COMT inhibitors

Answer 40

Always use with levodopa Reduces peripheral breakdown of levodopa Prolongs to motor response to levodopa

Question 41

List examples of dopamine receptor agonists

Answer 41

Ropinirole Amantadine Rotigotine Apomorphine – only for patients with severe motor fluctuations

Question 42

List side effects and contraindications of dopamine receptor agonists

Answer 42

Side effects: impulse control disorder, sedation, confusion, hallucination, hypotension, seizures Contraindications: epilepsy, gastric ulcer

Question 43

Describe monoamine oxidase B inhibitors

Answer 43

Rasagaline, selegiline Enhance dopamine Prolong action of levodopa but can be used alone Smooth out motor response

Question 44

Describe anticholinergics

Answer 44

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

Question 45

Describe amantadine

Answer 45

Mainly effective for levodopa induced dyskinaesia | Few side effects: hallucinations, confusion

Question 46

Describe clinical features of myasthenia gravis

Answer 46

Fluctuating, fatigable, weak skeletal muscle - extraocular muscles - bulbar involvement: dysphagia, dysphonia & dysarthria - limb weakness: proximal symmetric - respiratory muscle involvement

Question 47

Outline the therapeutic management of myasthenia gravis

Answer 47

``` Acetylcholinesterase inhibitors Corticosteroids – decrease immune response Steroid sparing – azathioprine IV immunoglobulin Plasmapheresis ```

Question 48

Describe acetylcholinesterase inhibitors

Answer 48

``` Pyridostigmine, neostigmine Enhance neuromuscular transmission Skeletal & smooth muscle Excess dose can cause depolarising block Muscarinic side effects – SSLUDGE ```

Question 49

List the muscarinic side effects

Answer 49

``` Salivation Sweating Lacrimation Urinary incontinence Diarrhoea GI upset and hypermotility Emesis ```

Question 50

Name 4 types of generalised seizures

Answer 50

Absence Myoclonic Tonic-clonic Atonic