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Stage 1 Seminar: Clinical Pharmacology of the Nervous System. Dr Fraz Mir Clinical Pharmacology Unit Department of Medicine University of Cambridge. Topics to be Covered. Anti-epileptic medicines Anti-parkinsonian drugs Anti-depressants And briefly – Anti-psychotics
Dr Fraz Mir
Clinical Pharmacology Unit
Department of Medicine
University of Cambridge
Mechanism of Action
inhibition of excitatory neurotransmitters
direct membrane stabilisation
stimulation of inhibitory neurotransmitters
Initiation of therapy
Seizure disorder Drugs of choice (1st choice in bold)
(grand mal) carbamazepine
blurred vision, diplopia,dizziness, bradycardia, skin rashes, GI upsets, osteomalacia, folate deficiency, hyponatraemia
primidone (largely metabolised to phenobarbitone)
sedation, folate-induced megaloblastic anaemia, ataxia
Agent mechanism comments
Vigabatrin structural analogue of GABA CNS effects
irreversible inhibition of causes weight gain
GABA-transaminase ` combination only
Lamotrigine membrane stabiliser by blocking voltage less CNS effects than older agents
dependent sodium channels maculopapular skin rash / SJ synd
secondary impaired release of excitatory mono or combination
Gabapentin GABA analogue but mechanism of action combination only
Topiramate blockade of voltage sensitive sodium adjunct in partial seizures
channels, enhanced GABA, glutamate inhibition
Oxcarbazepine similar to carbamazepine
Levetiracetam adjunct treat for partial seizures
Definition - generalised tonic-clinic fit lasting more than 30 minutes or repeated fits without recovery of normal alertness in between.
1. Establish airway, oxygenate, recovery position
2. Establish IV access and give IV lorazepam 2-4mg (IV diazepam 5-10mg alternative; Buccal midazolam 10mg preferred over rectal diazepam)
4. Check blood for: glucose, urea and electrolytes, Calcium, anticonvulsant levels, and arterial blood gas and pH.
5. Give 100mg IV thiamine if high risk of alcoholism (prevents precipitation of Wernicke’s) and if known to have brain tumour or active vasculitis give dexamathasone 10mg IV.
7. If continues to fit then load with phenytoin IV (increasingly replaced by its pro-drug, fosphenytoin, which is less cardiotoxic and causes fewer injection site reactions)
8. If still fitting then contact ITU (needs intubation and paralysis)
Thus: reduced dopaminergic activity
Increased cholinergic activity
Entacapone inhibits COMT
Selegeline MAO-B inhibitor
Amantadine – better known perhaps as anti-influenza agent (type A only).
Delay L-DOPA (and motor fluctuations and further loss of neurons). Balance the need of treatment with functional capacity
Eventually L-dopa can be started in standard or slow release formulations
Options (trialled in this order …)
chlorpromazine thioridazine olanzepine/flupentixol/haloperidol
Sedation +++ ++ +
Anti-cholinergic ++ +++ +
EPS ++ ++ +++
(c.f. serotoninergic syndrome)
Mild to moderate depression: avoid drugs with bad adverse effect profile (poor compliance likely)
Severe depression: drugs acting on both NA and serotonin
Length of drug-treatment
for control of mania/bipolar disorder
needs careful monitoring
beware - potent enzyme inducer!