MED2042 WEEK 3 - Pharmacology (Anticonvulsant drugs)
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- What is epilepsy?
- Epilepsy is a brief disorder of brain function associated with sudden abnormal discharge of nerves.
- Describe the classification of epilepsy.
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Partial:
- simple
- complex (reduced consciousness)
- secondarily generalised
Generalised: loss of consciouness
- Absence
- Tonic-clonic
- Tonic or Clonic or Atonic; Myoclonic
Status epilepticus: continuous succession of fits - What are the symptoms of Partial Seizures?
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Motor: e.g. "Jacksonian march"
Sensory: e.g. hallucinations of smell, taste, hearing
Psychic: e.g. "deja vu", automatism
Sensory/psychic symptoms common in temporal lobe epilepsy - What are the symptoms of Tonic-clonic (grand mal) seizures?
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- Mood change +/- aura
- Tonic muscle spasm, loss of consciousness
- Clonic stage:jerking, salivation, +/- incontinence
- Confusion/headache - What are symptoms of generalised seizures?
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Absence (petit-mal): starts in childhood, transient loss of consciousness but not posture (~10sec)
Myoclonic: jerking of limbs
Atonic: loss of posture - List the mechanisms of action of anticonvulsants.
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- Potentiate GABA; benzodiaszepines, barbiturates, gabapentin (?)
- GABA analogue: tiagabine
- Reduce GABA breakdown; vigabatrin, balproate (?)
- Block Na+ channels; carbamazepine, phenytoin, topiramate - How do anticonvulsants work?
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Dose-related CNS depression (all anticonvulsants)
Cortical (sedation):
e.g. benzodiazepines & barbiturates
Cerebellar (ataxia, nystagmus, diplopia):
e.g. phenytoin - Describe the uses of different anticonvulsants.
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Valproate - most types (often used for generalised)
Carbamazepine, phenytoin - most types, except absence (carbamazepine often used for partial epilepsies)
Clonazepam - myoclonic, absence
Ethosuximide - absence
Vigabatrine, lamotrigine, gabapentin, topiramate, tiagabine, levetiracetam - "add on" therapy - Carbamazepine
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- Also used for trigeminal neualgia
- Liver enzyme induction
- Marrow depression, jaundice, gastrointestinal upset, rashes, hypersensitivity
- need to monitor blood - Phenytoin
-
- Narrow safety margin, cerebellar effects
- Phenytoin metabolism can become saturated with zero order kinetics
- Liver enzyme induction: drug interactions; folate, Vit D & neonatal Vit K deficiency
- Rashes, marrow depression, lymphadenopathy
- Costmetic effects: gum enlargement, acne, hairiness, coarse features - Vigabantrin, lamotrigine, gabapentin, topiramate, tiagabine, levetiracetam
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- For epilepsy uncontrolled by other drugs
- All cause CNS effects
Vigabatrin - GI upset, behavioural problems
Lamotrigine - Rashes
Gabapentine - GABA analogue; headache, tremor
Topiramate - like phenytoin but simplet
pharmacokinetics & less adverse effects; teratogenic
Tiagabine: GABA analogue; causes drowsiness and confusion
Levetiracetam: inhibits burst firing; dizziness, sedation - Ethosuximide
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- Used only for absences
- Rashes GI upset, marrow depression - Long-acting barbiturates (e.g. phenobarbitone)
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- 2nd choice drugs, dangerous in overdose
- sedation, learning problems
- rashes
- liver enzyme induction - Valproate
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- Gastrointestinal upset, marrow depression
- Severe hepatitis (rare, usually in children with other medical problems)
- Hair loss - Benzodiazepines
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Clonazepam:
- especially useful in myoclonic, absence
- sedation
Diazepam:
- i.v. in status epilepticus - Describe the drug interactions of anticonvulsants.
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Pharmakokinetic:
Liver enzymes not always predictable:
- competing drugs: increases drug levels e.g. valproate & phenobarbitone
- Enzyme induction: reduces drug levels e.g. warfarin, steroids, contraceptives
Protein binding sites:
e.g. salicylates & phenytoin
Pharmacodynamic:
e.g. interaction with other CNS depressants - Describe the link between pregnancy and anticonvulsants.
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- Anticonvulsants cause abortions & fetal abnormalities
- Phenytoin affects palate, heart ? due to reduced folate & Vit K
- Valproate causes spina bifida
- Withdrawal of anticonvulsants dangerous
- Phenytoin, topiramate & valproate are particularly likely to cause problems - Describe the aim of treatment of epilepsy.
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- Treat the whole person (including social and psychiatric problems)
- Remove causal/precipitating factors
- Prevent fits by drugs
- Minimise adverse effects
- Monotherapy preferable - What should be done if there is difficulty controlling fits?
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- Right diagnosis/drug?
- Monitor plasma levels:
> patient compliance?
> in therapeutic range?
- Dose requirements variable
- Never withdraw drug suddently:
> may get status epilepticus