Drugs used to treat epilepsie (Anti-epileptic drugs/ AED)
- Reduce pre-synaptic excitability
a. Voltage-gated Na+ channel antagonist (carbamazepine, lamotrigrine)
b. Voltage-gated K+ channel agonist (retigabine) - Stops neurotransmitter release
a. SV2A vesicle antagonist (levetiracetam)
b. Voltage-gated Ca2+ channel antagonist (pregablin and gabapentin) - GABA-ergic system agonists
a. GABA metabolism inhibitor (valproate, vigabatrin)
b. GABA transporter antagonist (tiagabine) - Reduces post-synaptic excitability
a. GABA receptor agonist (benzodiazepines)
b. AMPA and NMDA receptor antagonist
Carbamazepine Mechansm of action
- voltage gated Na+ channel blocker on pre-synaptic membrane
- Na+ influx increases excitability and drives action potentials
- Drug bloks the Na+ influx, reduces neuronal excitability and decreased the action potential
Carbamazepine
Pre-synantic Na+ channel blocker
Carbamazepine indications
epilepsy, trigeminal neuralgia, neuropathic pain
Side effects of carbamazepine
Dizziness Dry mouth Ataxia Fatigue Headache Diplopia Blurred vision Hyponatraemia Stevens-Johnson’s syndrome (rarely
Important PK/PD of carbamazepine
Response to the drug can be variable
Enzyme inducer of cytochrome P450; induces metabolism of itself
Interactions with other anti-convulsants
The transporter that can confer drug resistance is RALBP1
Grapefruit can significantly increase serum levels of this drug
HLA-B*1502 allele raises the risk for SJS; avoid in these patients
Patient information of carbamazepine
Avoid alcohol
Avoid grapefruit juice
Retigabine
Pre-synaptic K+ channel agonist
Mechanism of action of retigabine
- voltage gated K+ channel agonist on pre-synaptic membrane
- K+ efflux reduces neuronal excitability
- Drug increases the channel activity reducing the action potential
Phenytoin
Pre-synaptic sodium channel blocker
Phenytoin mechanism of action
- Acts as a voltage-gated Na+ channel blocker on the pre-synaptic neuronal membrane
- Limits action potential transmission
- Hence limiting spread of seizure activity
Indications for phenytoin
epilepsy (including status epilepticus
trigeminal neuralgia
Side effects of phenytoin
MORE THAN CARBAMAZEPINE Insomnia Headache Rash Constipation Vomiting Gingival hyperplasia Liver damage
Stevens-Johnson Syndrome (rare)
Leucopenia (rare)
Thrombocytopenia (rare)
Important PK/PD of phenytoin
Enzyme inducer of cytochrome P450
Can cause interactions with other anti-epileptic drugs
Narrow therapeutic index
Relationship between dose and plasma concentration is non-linear
Patient information for phenytoin
Avoid alcohol
Do not take calcium, aluminum, magnesium or iron supplements within 2 hours of ingestion
Take with food to reduce irritation
Levetiracetam
Reduces neurotransmitter release by blocking SVA2
Levetiracetam mechanism of action
- SV2A is a synaptic vesicle protein required for neurotransmitter release
- Levetiracetam blocks this and reduced neurotransmitter release
- Induces an anti-epileptic effect
Levetiracetam indication
epilepsy
Side effects of levetiracetam
Headache Fatigue Anxiety Irritability Drowsiness Constipation
Important PK/PD of levetiracetam
- Rapidly and almost completely absorbed after oral administration (99%)
- Food does not affect bioavailability
- Cytochrome P450 is not involved in its metabolism
Patient information of levetiracetam
- It might affect your ability to drive or operate machinery
- Not recommended during pregnancy and breastfeeding
Pregablin and gabapentin
Blocks voltage gated Ca2+ channels to decrease neurotransmitter release
Mechanism of action of pre-gablin
- ca2+ influx drivers neurotransmitter release
- Channel inhibited by pregablin and gabapentin
Tiagabine
Gabaergic system - GABA transporter
Tiagabine mechanism of action
- removes GABA from the synapse
- inhibited by tiagabine (to elevate GABA levels)
Valproate
GABAergic system - GABA metabolism
Valproate mechanism of action -
- degrades GABA transaminases
- inhibited by valproate (to elevate GABA levels)
Perampanel, felbamate and topiramte mechanism of action
Reduce post-synaptic effects
- glutamate receptors are not selectively targeted by an approed AEDs
- permapanel has main aactivity blocking AMPA receptors
- Felbamate has weak affinity for NMDA receptors
- Topirmate binds both AMPA and kainate receptors
Benzodiazepines mechanism of action
Reduces neuronal excitability
- GABAa receptor activity increased
- Increase the frequency of channel openin which leads to increase in chloride ion conduction and inhibitor of the action potential
Drugs for localised onset
lamotrigine, carbamazepine
Drugs for generalised onset
Valproate, levetiracetam, lamotrigine
Drugs used to treat parkinsons
Drugs that increase dopaminergic activity
a. dopamine precursors
b. dopamine agonists
c. drugs that stimulate dopamine release
d. MAO-B inhibitors
Drugs that inhibit strialtal cholinergic activity
a. anticholingeric agents
Example of dopamine precursor
- Levodopa
Mechanism of action of L-dopa
- Immedaite precursor of dopamine
- Able to cross the blood-brain barrier to replenish dopamine content of the corpus striatum
- L-dopa is decarboxylated to dopamine to dopamine in the brain by Dopa decarboxylase
- beneficial effects on the actions of D2 receptors
Indication of levodopa
parkinsons disease
Side effects of levodopa
dyskinesia compulsive disorders hallucinations nausea GI upset
Important pharmacokinetics/ pharmacodynamics for l-dopa
- Converted to dopamine in peripheries (which can cause the motor side effects)
- Given with a dopamine decarboxylase inhibitor or COMT inhibitor to reduce these effects
- Short half life – 50 to 90 mins
- Rapidly absorbed from the proximal small intestine via the large neutral amino acid (LNAA) transport carrier system
Patient information for l-dopa
- Dyskinesia common
- Reduced efficacy over time
- Avoid abrupt withdrawal
Dopamine Agonists examples
Rotigotine
Bromocriptine
Apoorphine
Pramipexole
Mechanism of action of dopamine agonists
Dopamine agoinsts selective for the D2 receptor in the CNS
Inhibits the release of prolactin from the anterior pituitary gland
Duration longer than L-dopa
Stiulates post synaptic dopamine receptors
Apomorphine works also at D2 receptor- non selective
Pramipexole: selective D3 receptor
Indication for dopamine agonists
Parkinsons disease
Side effects of dopamine agonists
apopmorphine: pain at site of injection, nausea, vomitting
Pramipexole; hllucinations, nausea, drowiness, involuntary movements
Important PD/PK of dopamine agonists
Apomorphine: highly emetic, hence limited use. Short half life (40 mins). Needs to be given via injection.
Pramipexole: Cimetidine increases its toxicity, long half life (8 hrs)
Dopamine Agonists have reduced efficacy over time
Patient information for dopamine agonists
Apomorphine can only be injected
Dopamine agonists are weaker then L-DOPA so treatment may be modified in time.
Catechola-o-methyl transferase inhibitor
Entacapone
Mechanism of action of entacapone
Prevents the peripheral breakdown of levodopa by inhibiting COMT (COMT converts L-DOPA into 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD). 3-OMD doesn’t cross the blood brain barrier).
Therefore more levodopa reaches the brain
Indication of catechol-o =-methyl transferase inhibitor
Parkinson’s Disease in conjunction with L-DOPA and dopamine decarboxylase inhibitor
Side effects of catechol-o-methyl transferase inhibitor
Dyskinesia (common, up to 27%) Nausea (11%) Abdominal pain Vomiting Dry mouth Dizziness
Important PK/PD of catechol-o-methyl transferase inibitor
Rapidly absorbed
Levodopa dose may need to be reduced by 10-30% when given with Entacapone
Patient information of catechol-methyl transferase inhibitor
- Urine may turn brown – normal
- Could become lightheaded/dizzy while doing daily activities
- Avoid abrupt withdrawal
Selegiline, rasagiline
MAO-B inhibitor
Mechanism of action of selegiline, rasagiline
- prevents dopamine breakdown by binding irreversibly to monoamine oxidase
- can be prescribed as monotherapy in early disease or as adjunct in later disease
- well tolerated