ACEM Primary
Anticonvulsant Pharmacology
Phenytoin
- Oldest non-sedative anti-seizure drug
- MOA: Block Na + channel-> inhibit membrane potential
- P’kinetics:
- PO or IV (fosphenytoin)
- Highly bound albumin
- Plasma level will decrease in hypoalbuminaemia or uremia
- Displaced by other drugs (sulfonamides)
- Affinity for thyroid binding globulin (can confuse TFT)
- Drug concentration in CSF µ plasma
- Accumulates in brain, liver, muscle and fat
- Metabolised in liver, excreted by kidney
- Elimination is dose dependent = low blood levels is first order-> at therapeutic levels, maximum capacity of liver to metabolise is reached. Any further increases-> toxicity.
- t ½ = 12-36 hours
- Therapeutic range 10-20 mcg/mL
- Toxicity short term = nystagmus, abnr EOM, diplopia, ataxia. Long term = osteomalacia, peripheral neuropathy
Carbamazepine
- Non-sedative, initially developed for trigeminal neuralgia
- MOA = block Na+ channels-> inhibit high frequency repetitive neuronal firing
- P’kinetics:
- Peak levels 6-8 hours
- 70% bound plasma proteins, nil displacement by other drugs
- Vol distribution 1L/kg
- Slow systemic clearance
- t ½ = 36 hours initially, 8-12 hours long term
- Metabolised in liver, interactions-> phenytoin/ phenobarb induce enzymes thus decrease carbamazepine level, valproate inhibits clearance
- PO form, daily dose 1-2g for adults
- Therapeutic level = 4-8 mcg/mL
- Toxicity = diplopia, ataxia, blood dyscrasias (rare)
Sodium valproate
- Valproic acid at body pH
- MOA = block Na+ channels-> inhibits high frequency, repetitive neuronal firing + blocks GABA breakdown + inhibits histone deacetylase causing change in gene transcription
- Effective against tonic clonic, absence, myoclonic seizures
- P’kinetics:
- Bioavailability >80%
- Peak blood levels ~2 hours
- Food delays absorption
- 90% bound to plasma proteins
- Vol of distribution = 0.15L/kg (confined to ECF)
- t ½ = 9-18 hours
- Clearance dose dependent
- Therapeutic level = 5-100mcg/ mL
- Dose 25-30mg /kg/ day
- Interactions = valproate displaces phenytoin from plasma proteins + inhibits metabolism of phenobarbital, phenytoin, carbamazepine
Toxicity = NV, GI upset, reflux, fine tremor, weight gain, increase appetite, hair loss, hepatotoxicity, thrombocytopaenia
Neurotransmitters
| AMINO ACIDS | |
| Glutamate | Acidic Excitatory In relay neurons at all levels + interneurons Acts at R AMPA, KA, NMDA MOA: Release into synaptic cleft by Ca2+ dependent exocytosis-> acts at post synaptic R-> reuptake by glutamate transporters into glia-> converted to glutamine by glutamine synthetase-> released by glia and taken in nerve terminal-> converted into glutamate by glutaminase and concentrated in vesicles by VGLUT. |
| GABA/ glycine | Neutral Inhibitory In interneurons in spinal cord and brainstem Two R GABA-A and GABA-B = coupled to G proteins which depending on location inhibit Ca2+ or stimulate K+ channels = inhibitory post synaptic potential. |
| Acetylcholine | Present in cell bodies at all levels Muscarinic, nicotinic R |
| MONOAMINES | |
| Dopamine | Cell bodies at all levels Major pathways linking substantia nigra to neostriatum and ventral tegmental region to limbic structures 5 DA R General inhibitory action via Gi coupled protein |
| Norepinephrine | Cell bodies in pons, brains project to all levels Most in lateral tegmental area of reticular formation Adrenergic R a/b |
| 5-Hydroxytryptamine (Serotonin) | Cell bodies in mid-brain and pons project to all levels Originate from neurones in midline raphe nucleus of pons 5-HT1A inhibitory 5-HT2A excitatory 5-HT3 excitatory (ondansetron is an antagonist here) 5-HT4 excitatory |
| Histamine | Cells in ventral posterior hypothalamus H1/ H2 excitatory, H3 inhibitory |
| NEUROPEPTIDES (packaged in large dense vesicles) | |
| Substance P | Small unmyelinated sensory neurons in spinal cord and brainstem Transmit noxious stimuli – pain |
| Opioid peptides | Cell bodies at all levels, long and short connections Inhibitory |
| OREXINS | Cell bodies in hypothalamus, project widely Excitatory, glutamate co-release Promote wakefulness |
| OTHER | |
| Endocannabinoids | Widely distributed Inhibitory R called CB1, mainly presynaptic terminals Affect memory, cognition and pain pathways |
| NO | Unclear function Nitric oxide synthase is activated by calcium- calmodulin via NMDA R |
| Purines | ATP, UTP, UDP |
Last Updated on August 12, 2021 by Andrew Crofton
Andrew Crofton
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