Week 17 Pharmacology

Review of seizure types.

  • Partial
    • Simple
    • Complex
    • Partial seizures which are secondarily generalised
  • Generalised
    • Tonic clonic
    • Absence – 2-3Hz spike and wave pattern in EEG
      • Responds to ethosuximide and valproate
      • Worsens with phenytoin and carbamazepine
    • Tonic
    • Clonic
    • Clonic and myoclonic
    • Infantile spasms

 

Diazepam / Midazolam

  • Mechanism of action
    • GABA – receptor agonist (Cl channel) and potentiate GABAergic inhibition in CNS. Membrane hyperpolarisation.
    • SE – sedation, resp depression, cardiovascular depression at toxic doses esp if hypovolaemic/CCF
    • Flumazenil – GABA antagonist to reverse the effects
    • Sedation and tolerance limits benzodiazepine use
    • All benzodiazepines have hepatic metabolism and excreted in urine

 

Diazepam

  • Potentiates GABA-a response
  • Highly effective in stopping continuous seizure activity, esp tonic clonic status epilepticus
  • Tolerance develops for diazepam if given long term.
  • PK – well absorbed, 90% bioavail, peak 1hr, highly protein bound, metabolised a lot to several active metabolites, T 1/2 – 2d

 

Clonazepam

  • Long acting, effective against absence seizures and some myoclonic seizures, quite potent, sedative, no active metabolites but extensively metabolised. Bio avail 80%, T 1/2 20-50hrs

 

Phenytoin

  • Pharmacodynamics
    • Alters Na(blocks Na Channel),K,Ca conductance, membrane potentials, concentration of amino acids and neurotransmitters NA, Ach, GABA.
    • Block sustained high frequency repetitive firing of action potentials.
    • Used in partial and generalised tonic clonic seizures
    • Earliest non sedative anti epileptic
  • Pharmacokinetics
    • Nearly complete absorption in GIT
    • Peak plasma conc in 3-12hrs
    • Unreliable absorption with IM injection so precursor fosphenytoin used
    • 90% bound to plasma proteins
    • Accumulates in brain, liver, muscle and fat
    • Metabolised by liver into inactive metabolites
    • Excreted in urine
    • Small proportion excreted unchanged in urine
    • Dose dependent elimination (variable order kinetics), low levels – first order kinetics, saturation of hepatic metabolism –> zero order kinetics at higher levels WITHIN therapeutic range so even a small rise in dose after this can increase plasma concentration by large amount and rapidly lead to toxicity.
    • T 1/2 – 12- 36hrs, longer in high levels.
    • 4-6wks for blood levels to stabilise
    • Therapeutic range : 10-20mcg/ml
    • Start at 300mg/d
  • Toxicity
    • Nystagmus – early
    • Loss of smooth extraocular pursuit movements
    • Diplopia
    • Ataxia
    • Sedation
    • Gingival hyperplasia
    • Hirsuitism
    • Coarsening facial features
    • Peripheral neuropathy – diminished deep tendon reflex
    • Osteomalacia
    • Rash/hypersensitivity/fever/agranulocytosis
  • Interactions
    • Protein binding
      • other protein bound drugs can displace phenytoin – eg sulfonamides,
      • Hypoalbuminaemia
      • Renal diseases – The plasma protein binding of phenytoin may be significantly decreased in patients with renal impairment, resulting in elevated free drug concentrations and increased risk of toxicity.
    • Interacts with TFT testing (TSH is the most reliable within it)
    • Induces microsomal enzymes in liver –> increase bd of other drugs

 

 

Carbamazepine.

  • Tricyclic effective in Bi polar depression, non sedative, uses – trigeminal neuralgia, mania.
  • PD
    • Blocks Na channels and inhibits high frequency repeptive firing neurons ( like phenytoin!)
    • Acts presynaptically to decrease synaptic transmission
  • PK
    • Rate of absorption varies
    • Almost complete absorption
    • Peak level 6-8hrs
    • Food slows absorption
    • Distribution is slow
    • Vd 1L/kg
    • 70% bound to plasma protein – doesn’t displace other drugs from the protein
    • Low systemic clearance at start. T1/2 36hrs at start then 8-12hrs when on cont therapy
    • Induces microsomal enzymes of liver
    • Completely metabolosed, has one metabolite with anticonvulsant activity
    • Theraputic trough level 4-8mcg/ml
    • Drug interaction
    • Due to enzyme induction
    • Increase metabolism of phenytoin, ethosuximide, valproate, clonazepam, these other drugs can also induce enzymes and cause carbamazepine to have lower concentrations.
  • Toxicity
    • Diplopia
    • Ataxia
    • GI upset
    • Unsteadiness
    • Drowsy at high doses
    • Idiosyncratic blood dyscrasias – aplastic anaemia, agranulocytosis
    • Rash

 

Sodium valproate.

  • PD
    • Blocks sustained high frequency firing neurons
    • Affects sodium currents (partial seizure prevention)
    • NMDA blockade
    • Increased GABA levels – unclear how
    • Inhibit histone deacetylase – inhibit transcription of some genes
    • Effective in tonic clonic esp the primarily generalised ones.
    • Very effective against absence seizure, esp if pt has concommitant tonic clonic seizures.
    • Can control some myoclonic seizures and some partial seizures.
    • Other uses – bi polar, migraine prophylaxis
  • PK
    • Fully ionised at normal pH
    • Action is poorly corelated with plasma concentration, peak blood levels within 2hrs
    • Well absorbed
    • Bioavailability >80%
    • 90% bound to plasma protein
    • Vd – extracellular water 0.15L/kg
    • Measure total and free drug levels cos at higher doses there is more free valproate
    • Slow clearance and dose dependent clearance. T1/2 varies from 9hrs – 18hrs.
    • 20% excreted as direct conjugate of valproate.
    • Therapeutic 50-100mcg/mL – dose required to achieve this can vary.
  • Drug interaction
    • Displaces phenytoin from plasma proteins
    • Inhibits metabolism of phenytoin, carbamazepine, phenobarbitol
    • Decrease clearance of lamotrigine.
  • Toxicity
    • Most common – Nausea, vomiting, abdo pain, heart burn – so start slowly
    • Sedation
    • Tremor, wt gain, increased appetite, hair loss
    • Idiosyncratic – hepatotoxicity(severe)esp in toddlers and ppl on multiple meds. NEEDS LFT monitoring when starting.
    • Teratogenocity – Spinabifida in babies – adviced against in pregnancy if possible.

 

Phenobarbitone

  • PD – Enhances phasic GABA-a receptor responses, reduces excitatory synaptic responses
  • Uses – genrealised tonic clonic, partial seizures, myoclonic seizures, neonatal seizures, status epilepticus.
  • Pk – nearly complere absorption, NOT significantly plasma protein bound, peak concentration 0.5-4hrs, no active metabolites, t 1/2 varies from 75-125hrs.
  • Toxicity – sedation, ataxia, hyperactivity in children, cognitive issues

 

Paraldehyde.

Today, paraldehyde is sometimes used to treat status epilepticus. Unlike diazepam and other benzodiazepines, it does not suppress breathing at therapeutic doses and so is safer when no resuscitation facilities exist or when the patient’s breathing is already compromised. This makes it a useful emergency medication for parents and other caretakers of children with epilepsy. Since the dose margin between the anticonvulsant and hypnotic effect is small, paraldehyde treatment usually results in sleep

 

Lamotrigine

  • Prolongs inactivation of voltage gated Na channels
  • Acts on presynpatic Ca channels and decreases glutamate release
  • No sig protein biding, t 1/2 25-35hrs, no active emtabolites
  • Used in general, partial and absence seizures

 

Vigabatrin.

  • Irreversibly inhibits GABA transaminase
  • Not bound to plasma proteins, 70% bioavail, not metabolised, t 1/2 5-7d
  • Used in partial seizures and infantile spasms

 

Viva questions:

  • Tell me about Phenytoin.
  • Tell me about the PK of Phenytoin.
  • Tell me about Phenytoin toxicity.
  • What drugs are of use in status epilepticus ? Remember to include oxygen and Thiopentone in your initial list.
  • Tell me about carbamazapine
  • Tell me about Sodium Valproate