Week 10: Treatment of Neurological Disorders Flashcards
Define and classify seizures
Seizures may result as a consequence of a medical condition affecting the brain (secondary – about 1/3), or as an inherent tendency of an individual towards seizures (primary-about 2/3). It is always important to consider secondary causes of convulsions when assessing patients presenting with fits. A useful clinical classification of fits divides them into 2 main categories:
- Partial Seizures: here, the discharges begin in a localised area of the brain. Thus, the symptoms reflect the area affected, but might include abnormal sensations or thoughts, a change in behaviour, or an involuntary motor action.
- Generalised Seizures: the whole brain is affected, including the reticular system, and there is immediate loss of consciousness. These are further divided into the tonic-clonic seizure and the absence seizure. Tonic clonic seizures are described below and are the most dramatic.
A seizure may have no antecedent (especially in primary epilepsy) but many conditions are associated with either a fit in a person who does not have epilepsy, or the lowering of the fit threshold in those that do.
Relevant conditions to consider when appropriate include:
Head injury (traumatic or "chemical" Drugs and alcohol Hypoglycaemia Infections (especially CNS but elsewhere too), particularly in children CVA / subarachnoid haemorrhage etc Metabolic disturbances Poor compliance with AED therapy
Uncontrolled epilepsy is not a benign condition. Whilst individuals with rare fits can lead essentially normal lives, those with severe disease can have significant morbidity and mortality. Some of these are a result of:
Status epilepticus in particular is a life and brain threatening emergency
Physical injury through a seizure (fall, accident etc)
SUDEP – sudden death in epilepsy
Significant adverse reactions to medication
Association with higher risk of serious psychiatric disease
Association of cognitive impairment (in those with serious seizures)
Stigma associated with epilepsy
The mechanisms of action of the AEDs are described by the known pharmacology associated with what targets?.
Enhancement of GABAA Action (benzodiazepines, phenobarbitone but ironically not gabapentin!)
Inhibition of sodium channel function (phenytoin, valproate, carbamazepine, lamotrigine)
Inhibition of calcium channel function (ethosuximide, gabapentin) Inhibition of glutamate release or function
List some common anti epileptic drugs.
- Carbamazepine
- Valproate Sodium
- Benzodiazepines
- Phenytoin
- Lamotrigine (increasingly first line nowadays)
for prescription of AED very basic rule of thumb would be to consider:
valproate sodium as first line therapy for primary generalized seizures,
carbamazepine for partial seizures (or generalized seizures).
lamotrigine can be used in either circumstances, and is probably the
drug of choice for women of childbearing age.
benzodiazepines and phenytoin are first line therapies for acute life
threatening status epilepticus. Phenytoin has non-linear kinetics and so can reach therapeutic (and toxic) levels rapidly.
AEDs and pregnancy
There is considerable difficulty in the management of women of child- bearing age and potential who also have epilepsy requiring pharmacological therapy. There are several points to consider regarding treatment:
The risk of seizures to mother and foetus if treatment is stopped. Careful history taking is required to ascertain the frequency and severity of seizures in the individual patient. Those with extremely rare and mild seizures might tolerate being off treatment during gestation quite well. Those with frequent fits run the risk of status epilepticus and harm to both themselves and the baby if treatment is stopped.
Certain anti-epileptics drugs have been associated with congenital malformations. The risk of foetal abnormalities in a normal pregnancy is about 2%. Valproate has been associated with about a 9% risk of foetal abnormalities, including neural tube defects, and possible learning difficulties later in life. Other monotherapy is associated with a doubling of the baseline risk of malformation.
what is status epileptics?
Status epilepticus is a prolonged seizure of any type. The most common and dramatic is convulsive status epilepticus, although non-convulsive status epilepticus also occurs. It is defined as either a single convulsion lasting > 30 minutes or convulsions occurring back to back with no recovery between them.
However, any convulsion lasting longer than 5 minutes or two convulsions without full recovery of consciousness in between should receive emergency treatment.
Uncontrolled convulsions can lead to hypoxia and irreversible brain damage or death
Outline emergency treatment protocol for seizures.
Priorities include airway protection, the delivery of supplemental oxygen, identification of the cause and its reversal, and the termination of the seizure as quickly as possible. Investigations should include a bedside glucose, a lab urea & electrolytes (U&Es) and calcium, blood gases and further tests (perhaps later) to ascertain underlying cause (e.g. CT/MRI head – especially in trauma or focal fits).
Treatment of the seizures is vital. First line treatment includes benzodiazepines (e.g. lorazepam) and then IV phenytoin. Phenytoin is not widely used for long term control but because of its zero order kinetics, a therapeutic level can be reached quickly. It is however, toxic and has a narrow therapeutic index. If these measures are failing, or if the patient’s airway is compromised, ITU referral and paralysis and intubation will be required.
Define Parkinsons disease
Parkinson’s disease (PD) is a neurodegenerative disorder that has a progressive clinical course. It is characterised by motor and non-motor symptoms. The motor symptoms include; tremors, rigidity, bradykinesia and postural instability. These relate to low dopamine levels through loss of dopaminergic neurones and disturbances to other neurotransmitter levels.
How does Levodopa exert its effect?
Levodopa (L-DOPA) is a precursor to dopamine. It is used as it is able to cross the blood brain barrier, whereas dopamine cannot. L-DOPA has a half-life of 2 hours and thus requires a short dose interval. It is estimated that less than 1% enters the CNS. L-DOPA must then be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine. However with fewer remaining cells it is less reliable and prone to motor fluctuations.
To date dopamine receptor agonists while being direct acting have a lower efficacy than L-DOPA, but do exhibit less motor complications.
In contrast both MAOI type B inhibitors and COMT inhibitors act by prolonging the presence of dopamine by blocking its metabolism,
What causes Epilepsy?
Increase in Cerebral Neurone Excitability either by : - • Increased Excitation • Decreased Inhibition • Loss of Homeostatic Control • Spread of Neuronal Hyperactivity
Epilepsy : Classification TWO main types
- FOCAL seizures –(previously named PARTIAL) affect one (unilateral) hemisphere
- GENERALISED seizures – affect both (bilateral) hemispheres
what are they types of Focal seizures and mechanism?
- Simple focal - but remaining conscious
- Complex focal with impaired consciousness
- Focal with progression to generalised seizure
Mechanism
• Increased discharges in a focal cortical area e. g frontal, temporal, occipital lobes
symptoms of Focal (Partial) seizures
Symptoms reflect area affected • Involuntary motor disturbance • Behavioural change • Impending focal spread accompanied by ‘Aura’ eg unusual smell or taste, déjà vu / jamais vu, e.g. Temporal lobe • May become secondarily generalised
describe the mechanism of Generalised Seizures
- Generated centrally and spread through both hemispheres with loss of consciousness via ↓Reticular Arousal Centre
- Tonic-clonic seizures (“GRAND MAL”) 60%
- Absence seizures (“PETIT MAL”) 5%
- Many other types recognised e.g. Tonic, atonic, myoclonic
“GRAND MAL” Sequence (tonic-clonic convulsions)
- Aura - few seconds – strange smell or feeling
- Tonic Phase –10 to 30 secs ; unconscious, fall down, tonic muscle contraction with arms flexed, legs extended, respiratory spasm, cyanosis
- Clonic Phase - 1-5 minutes -violent jerking of face and limbs, tongue biting, mouth foaming, incontinence and potential for injury
- Post-ictal Phase – minutes to hours: flaccid limbs, deep coma, headache , confusion, slow reawakening
“PETIT MAL” Sequence (Absence Seizures)
- Often short duration (seconds)
- Normal activity ceases with blank stare, failure to respond, maybe eyes rolling, followed by rapid return to normal state
- Often brief and not noticed by others
- More common in children and adolescents
what is Status Epilepticus?
• Most seizures are short lived ( up to 5 mins)
• But some are prolonged or repeated frequently
without recovery interval
• Referred to as Status Epilepticus
• Treat as a Medical Emergency
• Untreated Status Epilepticus can lead to brain damage (by hypoxic encephalopathy)
or death (SUDEP)
Dangers of Severe Epilepsy
Uncontrolled epilepsy is not a benign condition • Physical injury relating to fall /crash
• Hypoxia – respiratory muscles in spasm
• SUDEP – sudden death in epilepsy
• Varying degrees of brain dysfunction/damage • Cognitive impairment
• Serious psychiatric disease
• Significant adverse reactions to medication
• Stigma / Loss of livelihood / life changing event
Epilepsy : Aetiology
Primary
• No identifiable cause (as yet) – “idiopathic”(70%) • Channelopathies (ion channel mutations) Secondary
• Medical conditions affecting brain ( 30%)
Vascular disease
Tumours
In elderly (60+) secondary metastases responsible for 60% seizures – important diagnostically
Epilepsy: Seizure Triggers
Sensory stimuli:
• eg flashing lights/strobes / other periodic sensory stimuli Brain Disease/ Trauma:
• Brain Injury
• Stroke / Haemorrhage
• Drugs/Alcohol
• Structural abnormality/Lesion
Metabolic disturbances
• Hypo– glycaemia /calcaemia / natraemia Infections
• Febrile convulsions in infants Therapeutics
• Some drugs can lower fit threshold
• AEDs + Polypharmacy: PKs may lower levels
Therapeutic Targets for AEDs
- Voltage Gated Sodium Channel Blockers
* Enhancing GABA Mediated Inhibition
Mechanism of VGSC Blockers
- Local loss of membrane potential homeostasis starts at focal point
- Relatively small number of neurones form generator site
- Neurones heavily depolarise
- Hyperactivity spreads via synaptic transmission to other neurones
VGSC Blockers reduce probability of high abnormal spiking activity
• With VGSC Blocker – gets access to binding site only during depolarisation - hence voltage dependent!
• Prolongs inactivation state – firing rate back to normal
VGSC blockers: Carbamazepine, Pharmacology and pharmacokinetics
Pharmacology:
• Carbamazepine prolongs VGSC inactivation state Pharmacokinetics:
• Well absorbed 75% protein bound – Linear PK
• Initial t1/2 = 30 hrs but strong inducer of CYP450 (3A4). • Affects its own Phase 1 metabolism
• Repeated use t1/2 = 15 hrs.
ADRs
VGSC blockers: Carbamazepine, ADRs and DDI
ADRS
• Wide ranging Type As: CNS - dizziness drowsy ataxia motor disturbance numbness tingling
• GI - upset vomiting
• CV – can cause variation in BP
• Contraindicated with AV conduction problems
• Others: Rashes Hyponatraemia
• Rarely: Severe bone marrow depression – neutropenia
DDIs
• Because CYP450 inducer can affect many other drugs
• Phenytoin (AED) ↓ + PK binding - CBZ plasma conc. ↑ • Warfarin ↓
• Systemic Corticosteroids ↓
• Oral contraceptives ↓
• Antidepressants - SSRIs MAOIs TCAs & TCA • interfere with action of Carbamazepine
Epilepsy types treated with Carbamazepine and Phenytoin
- Generalised Tonic - Clonic
- Partial - All
- Not Absence Seizures
VGSC blockers: Phenytoin Pharmacology and pharmacokinetics
Pharmacology:
• Phenytoin prolongs VGSC inactivation state
Pharmacokinetics:
• Well absorbed – but 90% bound in plasma competitive binding can increases levels (see DDIs)
• Also CYP450 inducer (CYP3A4 - not CYP2C9 & CYP2C19 which metabolise Phenytoin)
• Sub-therapeutic concs linear PK but NON-LINEAR PK at therapeutic concns - very variable t1/2 = 6-24 hrs
VGSC blockers: Phenytoin ADRs and DDIs
ADRs
Very wide ranging Type A’s: CNS – dizziness ataxia headache nystagmus nervousness
• Gingival Hyperplasia (20%) • Rashes - Hypersensitivity
• + Stevens Johnson (2-5%) DDIs
• Competitive binding eg with Valproate (AED) NSAIDs/salicylate increases plasma levels- exacerbates Non-Linear PKs
• Very wide range of interactions including
• Oral Contraceptives ↓
• Cimetidine - Phenytoin ↑
VGSC blockers: Lamotrigine Pharmacology and pharmacokinetics
Pharmacology:
• Lamotrigine (LTG) prolongs VGSC inactivation state • Ca2+ channel blocker & Glutamate release ↓? Pharmacokinetics:
• Well absorbed – Linear PK t1/2 = 24 hrs (Phase II)
• No CYP450 induction → fewer DDIs
VGSC blockers: Lamotrigine ADRs and DDIs
ADRs
• Less marked CNS Dizziness ataxia somnolence
• Nausea. Still some mild (10%) and serious (0.5%) • skin rashes
DDIs
• Adjunct therapy with other AEDs.
• Oral Contraceptives reduce LTG plasma level
• Valproate ↑ LTG in plasma (competitive binding)
Epilepsy types treated with LTG
- Partial Seizures
- Generalised - Tonic-clonic and Absence Seizures and other subtypes
- LTG increasingly first line AED for Epilepsy
- Not first line paediatric use as ADRs ↑
- Appears safer in pregnancy ?
Enhancing GABA Mediated Inhibition - list the pharmacological targets
• Major role in post synaptic inhibition – 40% synapses in brain are GABA-ergic
• GABA↑ is natural anticonvulsant or excitatory ‘brake’ Distinct pharmacological targets I
Binding with GABAA receptor
• Direct GABA agonists
• Benzodiazepine Site – Enhance GABA action • Barbiturate Site – Enhance GABA action
General Mechanism
GABA Mediated Inhibition Enhancement
- Increased Chloride current into neurone - increases threshold for action potential generation
- Reduces likelihood of epileptic neuronal hyperactivity • Makes membrane Potential more negative
Enhancing GABA Mediated Inhibition Benzodiazepines
Pharmacology and pharmacokinetics
Pharmacology:
• Benzodiazepines (BZDs) act at distinct receptor site on GABA Chloride channel (see earlier slide)
• Binding of GABA or BZD enhance each others binding
• Act as positive allosteric effectors
• Increases Chloride current into neurone – increases threshold for action potential generation
Pharmacokinetics:
• Well absorbed 90-100% highly plasma bound 85-100% • Linear PK t1/2 vary 15-45 hrs
ADRs
Enhancing GABA Mediated Inhibition Benzodiazepines
ADRs and DDIs
ADRs • Sedation • Tolerance with chronic use • Confusion impaired co-ordination • Aggression • Dependence/Withdrawal with chronic use • Abrupt withdrawal seizure trigger • Respiratory and CNS Depression DDIs • Some adjunctive use • Overdose reversed by IV flumazenil but use may precipitate seizure/arrhythmia.
