Pharmacological Mx of epilepsy Flashcards
Epilepsy definition
Chronic neurological condition characterised by recurrent, unprovoked seizures
Types of epilepsy (onset) - two
- Focal - particular area in the brain from which seizure originate (e.g. hypocampus sclerosis due to meningitis, injury)
- Generalised - in all the areas of the brain
- unknown onset
What’s symptomatic vs idiopathic epilepsy?
Symptomatic - arise from an identifiable brain lesion
*usually focal that +/- generalise
Idiopathic - when an identifiable cause or structural lesion cannot be found (normal EEG, normal brain scan)
*usually generalised
*80-90% will achieve complete freedom from seizures
What’s the disadvantage of Phenobarbital? Do we prescribe it in the UK?
Phenobarbital is highly sedating -> we therefore do not prescribe it in the UK
* it is one of the oldest anti-epileptics
* it is one of the cheapest as well - some countries in the world still prescribe them a lot
The most common anti-epileptic drugs used (8)
- Lorazepam
- diazepam
- Phenytoin
- Valproate
- Clonazepam
- Carbamazepine
- Gabapentin
- Lamotrigine
Main MoA of anti-epileptic drugs (easy explanation - two types)
Remember: anti-epileptics either affect electrical current or neurotransmitter release (or both)
What do anti-epileptics do in terms of neuronal excitability and how do they do that?
Detailed: Reduce neuronal excitability
( Na+ and Ca++ channels)
Aim: to decrease depolarisation-induced Ca++ influx and vesicular release of neurotransmitters
What happens to Na+ channel at resting state? (in neuronal membranes)
They are closed -> ions are outside
What ions do get out of the cell and which ones go in?
Na+ go in
K+ go out
What do most anti-epileptic drugs do to the sodium channel?
They keep the Na+ gate closed (by increasing the rate of inactivation gate) -> so less Na+ ions will get into the cell
Simply: sodium channel blocker -> they reset electro-chemical gradient -> so to stop electrical impulse from starting one after another (across the neurones)
Just have a look at the pictures - MoA of anti-epileptic drugs
Some will inhibit passing on the action potential at different points at the pre-synaptic/ synaptic and post-synaptic
What is the general MoA of the drugs that are alternatives to usual anti-epileptics?
- usual anti-epileptics -> will reduce Glutamate (so reduce excitation of the neurones)
- alternatives -> will increase GABA -> so increase inhibition
What is MoA of GABA inhibitors?
They are allosteric modulators (increase) of GABAa receptor -> via the increasing frequency of Cl- channel opening -> prevents depolarisation -> less electrical firing
Benzodiazepines properties (6):
- sedatives
- anxiolytics
- muscle relaxants
- hypnotics
- anti- convulsant
- amnesic (e.g. Midazolam)
Phenytoin use (3)
Phenytoin
- Acute control of tonic-clonic seizures
- Rx of status epilepticus
- Prevention of seizures following neurosurgery or brain injury
Steps in acute Rx of status epilepticus
rectal diazepam/ IV lorazepam -> Phenytoin -> general anaesthetic
MoA of Phenytoin
Phenytoin
MoA: induces hyperpolarisation via sodium channels (blocks inactive Na+ channels) -> stabilises membranes -> prevents spread of seizure activity
Where is Phenytoin metabolised
95% in the liver
What’s meant by zero - order kinetics?
A constant amount of drug is eliminated (by enzymes) per unit time (so work in a predictable way) -> but that means that any increase in the dose will be not associated in an increase of the metabolism (therefore, an increase may lead to toxicity quickly)
Why do we need to do therapeutic drug monitoring on people on Phenytoin?
Because Phenytoin is metabolised by zero-order kinetics (enzymatic activity at a constant rate, does not increase with increased dose) -> therefore may lead to toxicity
What’s important to know about Phenytoin and COCP?
Phenytoin is CYP450 enzyme inducer -> so will cause more metabolism of combined oral contraceptive pill -> it will be less effective
What’s the brand name for sodium valproate?
‘Epilim’
What is Valproate used for? (2)
- Generalised or partial seizures
- Bipolar, anorexia, PTSD, migraine
How does Sodium Valproate work?
It is a sodium channel blocker and GABA transaminase inhibitor
What about women of reproductive age and Sodium Valproate?
They should never be given Valproate (as it is teratogenic) unless by an expert epileptologist
Adverse effects of Valproate
weight gain, GI disturbance (settles), tremor, SIADH, hyponatremia
What’s the brand name for Carbamazepine?
Tegretol
Use of Carbamazepine
Carbamazepine
- anti - epileptic
- trigeminal neuralgia
How is carbamazepine metabolised
almost completely by the liver
Does Carbamazepine stay given at the same dose?
We need to increase the dose with a time, because Carbamazepine stimulates upregulation of the genes that are responsible for its own metabolism -> as body will become ‘toned’ to it
What serious adverse drug reaction may happen with Carbamazepine? What populations are prone to it?
Steven Johnson Syndrome (SJS)
*more common in a Chinese population with HLA-B*1502 allele
What’s the brand name for Levetiracetam?
‘Keppra’
What is the advantage in use of Levetiracetam?
Levetiracetam = ‘ Koppra‘
It has a unique mechanism of action -> does not interact with other drugs
MoA: inhibits presynaptic Ca++ channels
Adverse effects of the use of Levetiracetam?
Increased risk of suicidal intention
Use of Vigabatrin
- licensed for infantile spasm
- add-on for refractory partial epilepsy where everything else has failed
What potential side effect of Vigabatrin use?
Permanent development of tunnel vision (by bilateral visual field constriction)
Lacosamide
- use
- MoA
- side effects
Lacosamide
Use: adjunctive therapy for partial seizures
MoA: enhances slow inactivation of Na+ channels -> sodium channel blocker
Side effects: dizziness and ataxia
Clobazam
- use
- class and its consequences
- advantages of use
Clobazam
Use:
- adjunctive therapy for seizures in those in whom monotherapy failed
- refractory epilepsy
Class: benzodiazepine -> cannot be used in long- term Rx due to development of tolerance
Advantage: It enhances GABAA receptors (like benzodiazepines) but has different allosteric binding sites -> less sedation/sleepiness
Why Lorazepam can be given only IV?
It is bound to protein = poor water and lipid solubility
