Epilepsy- Status epilepticus

Question 1

Benzodiazepines

Common indications

Answer 1

1. 1st line management of seizures and status epilepticus
2. 1st line management of alcohol withdrawal reactions
3. Sedation for interventional procedures
4. Short term treatment for severe, disabling or distressing anxiety
5. Short term treatment of severe, disabling or distressing insomnia

Question 2

Benzodiazepines

MOA

Answer 2

• The target of benzodiazepines is the γ-aminobutyric acid type A (GABAA) receptor. The GABAA receptor is a chloride channel that opens in response to binding by GABA, the main inhibitory neurotransmitter in the brain.
• Opening the channel allows chloride to flow into the cell, making the cell more resistant to depolarisation. Benzodiazepines facilitate and enhance the binding of GABA to the GABAA receptor.
• This has a widespread depressant effect on synaptic transmission. The clinical manifestations of this include reduced anxiety, sleepiness, sedation and anticonvulsive effects.
• Ethanol (‘alcohol’) also acts on the GABAA receptor, and in chronic excessive use, the patient becomes tolerant to its presence.
• Abrupt cessation then provokes the excitatory state of alcohol withdrawal. This can be treated by introducing a benzodiazepine (chlordiazepoxide), which can then be withdrawn in a gradual and more controlled way.

Question 3

BZ’s

Adverse effects

Answer 3

• Predictably, benzodiazepines cause dose-dependent drowsiness, sedation and coma.
• There is relatively little cardiorespiratory depression in benzodiazepine overdose (in contrast to opioid overdose), but the loss of airway reflexes can lead to airway obstruction and death.
• If used repeatedly for more than a few weeks, a state of dependence can develop. Abrupt cessation then produces a withdrawal reaction similar to that seen with alcohol

Question 4

BZ’s

Warnings

Answer 4

• The elderly are more susceptible to the effects of benzodiazepines so should receive a lower dose.
• Benzodiazepines are best avoided in patients with significant respiratory impairment or neuromuscular disease (e.g. myasthenia gravis).
• They should also be avoided in liver failure as they may precipitate hepatic encephalopathy; if their use is essential (e.g. for alcohol withdrawal), lorazepam may be the best choice, as it depends less on the liver for its elimination.

Question 5

BZ’s

Interactions

Answer 5

• The effects of benzodiazepines are additive to those of other sedating drugs, including alcohol and opioids.
• Most depend on cytochrome P450 enzymes for elimination, so concurrent use with cytochrome P450 inhibitors (e.g. amiodarone, diltiazem, macrolides, fluconazole, protease inhibitors) may increase their effects.

Question 6

Phenytoin

Common indication

Answer 6

1. To control seizures in status epilepticus where BZs are ineffective
2. To reduce the frequency of generalised or focal seizures in epilepsy, although drugs with fewer adverse effects and interaction e.g. valproate, lamotrigine, levetiracetam)

Question 7

Phenytoin

MOA

Answer 7

• The mechanism of action of phenytoin is incompletely understood. Phenytoin reduces neuronal excitability and electrical conductance among brain cells, which inhibits the spread of seizure activity.
• It appears to do this by binding to neuronal Na+ channels in their inactive state, prolonging inactivity and preventing Na+ influx into the neuron. This prevents a drift in membrane potential from the resting (−70 mV) to the threshold (−55 mV) value required to trigger an action potential.
• A similar effect in cardiac Purkinje fibres may account for both antiarrhythmic and cardiotoxic effects of phenytoin.

Question 8

Phenytoin

Adverse effects

Answer 8

• Long-term phenytoin treatment can cause a change in appearance, with skin coarsening, acne, hirsutism and gum hypertrophy.
• Dose-related neurological effects include cerebellar toxicity (e.g. nystagmus, ataxia and discoordination) and impaired cognition or consciousness.
• Phenytoin can cause haematological disorders and osteomalacia by inducing folic acid and vitamin D metabolism.
• Hypersensitivity reactions to phenytoin range from a mild skin rash to the rare life-threatening antiepileptic hypersensitivity syndrome (see Carbamazepine).
• Phenytoin toxicity (due to overdose or injudicious IV infusion) can cause death through cardiovascular collapse and respiratory depression.

Question 9

Phenytoin

Warnings

Answer 9

• Phenytoin is metabolised by the liver with zero-order kinetics (i.e. at a constant rate irrespective of plasma concentrations) for concentrations at or above the therapeutic range.
• Moreover, the therapeutic index is low, implying that the safety margin between therapeutic and toxic doses is narrow.
• Phenytoin dosage should therefore be reduced in hepatic impairment. In utero phenytoin, exposure is associated with craniofacial abnormalities and reduced IQ (fetal hydantoin syndrome).
• Women with epilepsy planning pregnancy should discuss treatment with a specialist and take high-dose folic acid before conception

Question 10

Phenytoin

Interactions

Answer 10

• Phenytoin is an enzyme inducer, so reduces plasma concentrations and efficacy of drugs metabolised by P450 enzymes, e.g. warfarin, and oestrogens and progestogens.
• Phenytoin is itself metabolised by these enzymes, so its plasma concentrations and adverse effects are increased by cytochrome P450 inhibitors, e.g. amiodarone, diltiazem and fluconazole.
• Complex interactions can occur with other antiepileptic drugs as most alter drug metabolism. The efficacy of antiepileptic drugs is reduced by drugs that lower the seizure threshold

Question 11

Phenytoin

Prescription

Answer 11

• LD dose IV- 20mg/kg
• PO phenytoin- 150-300mg daily, in 1-2 divided doses
• Phenytoin is adjusted according to plasma concentrations
• Phenytoin should not be stopped suddenly due to risk of seizure recurrence
• When switching between tabs and liquid bioavailability changes

Question 12

Phenytoin

Monitoring

Answer 12

• Plasma phenytoin concentrations measured immediately before the next dose should be 10–20 mg/L. If needed, make small changes in dose (e.g. by 50 mg) at a time, as zero-order kinetics makes the effect of change difficult to predict.
• After a dose change, wait at least 7 days before repeating blood tests to determine new steady-state plasma concentrations.
• Monitor efficacy by comparing seizure frequency before and after starting or changing treatment. Monitor blood pressure, cardiac rhythm, respiratory rate and oxygen saturations to look for adverse effects during IV treatment.