MOA of anti-epileptic drugs
- Enhancement of GABA action
- Inhibition of Na+ channels
- Inhibition of Ca2+ channels
Which drugs inhibit Na+ channels?
- Phenytoin
- Carbamazepine
- Lamotrigine
- Oxcarbazepine
- Valproate
Which drugs inhibit Ca2+ channels?
- Ethosuximide
- Valproate
Which drugs enhance GABA action?
- Barbiturates
- Benzodiazepines
- Gabapentin
MOA of phenytoin
Slows the rate of Na+ channel recovery following inactivation. Prevents the repetitive firing of neurons by selectively blocking of channels which are opening and closing rapidly.
Limited clinical use - unpredictable pharmacokinetics and drug interactions
Adverse effects of phenytoin
- Nystagmus
- Dipolpia
- Ataxia
- Headache, vertigo
- Confusion
- Skin rashes
- Anaemia
- Gum hyperlasia
MOA of Carbamaepine
Similar MOA to phenytoin, although structurally unrelated and has less drug interactions
Slows the rate of Na+ channel recovery following inactivation. Prevents the repetitive firing of neurons by selectively blocking of channels which are opening and closing rapidly.
Adverse effects of Carbamazepine
- Diplopia
- Ataxia
- Sedation (high doses)
- GIT upset
- Mental disturbances
- Water retention
- Aplastic anaemia
MOA of Ethosuximide
Specific for T-type calcium channels. Lowers T-type calcium currents in a dose dependent manner
No effect on sodium channels or at GABA neurons
Adverse effects of ethosuximide
- Nausea, vomiting
- Transient lethargy or fatigue
- Skin rashes
Indications for valproate
- Primary generalised seizures
- Simple and complex partial seizures
- Bipolar
MOA of Valproate
- Slows Na channel recovery from inactivation
- Limits activity of low threshold T-type calcium channels
- Increases activity of glutamic acid decarboxylase which increases the synthesis of GABA
- Inhibits activity of enzymes that degrade GABA
Adverse effects Valproate
- Nausea, vomiting
- Sedation, Increased appetite, weight gain
- Ataxia
- Hair loss, menstrual irregularities (infrequent)
Indication for Na+ channel inhibitors
Partial and generalised seizures
MOA Barbiturates
Acts on GABA A, chloride ion channel to increase the DURATION of opening
Phenobarbitone, primidone
Indication for Barbiturates
Limited clinical use due to availability of other drugs with lower toxicity and adverse effects
MOA of Benzodiazepines
Acts on GABA A chloride ion channels to increase the FREQUENCY of opening
Diazepam, Clonazepam*, midazolam
- Also inhibits T-type calcium channels
Indication for Benzodiazepines
Adjudicative treatment for epilepsy refractive to other antiepileptic drugs.
Acute treatment of seizures including status epilepticus
MOA of Gabapentin
- Lipophilic analogue of of GABA
- Does not act on GABA receptors
- Inhibits Na and Calcium channels
- Causes an increase in intracellular GABA levels in vitro
Adverse effects of Gabapentin
- Sedatin
- Dizziness
- Ataxia
- Fatigue
- GIT irritation
- Tremor
- Nystagmus
- Amnesia
MOA of levodopa
Levodopa can cross the BBB. It is a precursor of dopamine which is broken down to increase the dopamine levels
What is Levodopa co-administered with
Carbidopa or benserazide (dopa decarboxylase inhibitors)
These drugs do not cross the BBB. They prevent the breakdown of levodopa in the periphery to reduce the adverse effects and increase the concentration of dopamine in the brain
Adverse effects of levodopa
GIT –>
Catechol-O-Methyltransferase Inhibitor
Entacapone
MOA of entacapone
Prolongs the action of levodopa by reducing its peripheral metabolism. Through the blockade of dopa decarboxylase by the COMP pathway.
Decreases levodopa clearance and increases the relative bioavailability
Monoamine oxidase inhibitors
Selegiline, Rasagiline
Stalevo
Combination of carbidopa, levodopa and entacapone
MOA of monoamine oxidase inhibitors
- Selective for MAO-B which is mainly found in dopamine containing region of the CNS
- Protects endogenous dopamine from degradation and improves motor fluctuations
Amantadine
- 1st introduces as an antiviral drug
- Increases dopamine release and inhibits reuptake
- Less effective than Levodopa, loses efficacy with time
Muscarinic receptor antagonists (Parkinson’s Disease)
- Atropine, Benztropine
- Blocks the effects of ACh
- Used to treat tremors in Parkinsons
- Also used to treat patients taking anti-psychotic-like medication (DA agonists) that causes PD-like symptoms
Treatment of Huntington’s Disease
Drugs which block dopamine effective (dopamine receptor antagonists)
- Haloperidol, chlorpromazine
- Fluphenaine
Huntingtons results from:
Imbalance of dopamine (increased levels), ACh and GABA in basal ganglia
4 main classes of glutamate
- NMDA
- AMPA
- Kainate
- G-protein coupled receptors or metabotropic