Grimm Anti-convulsants
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- Definition of Primary Seizure
- idiopathic
- Definition of Secondary Seizure
- that occurs due to an underlying disease (i.e. renal, liver, CNS)
- Definition of Epilepsy
- recurring seizures
- Definition of Status epilepticus
- series of tonic-clonic seizures without return to consciousness
- Definition of Syncope
- sudden loss of consciousness and is due to a loss of blood flow to brain⬦NOT A TYPE OF SEIZURE
- Phenobarbital has a long half-life relative to its dosing interval (35-75 hr. and 12 hr. respectively). Explain the significance of this with respect to the peak and trough concentration observed. Compare to a drug w/ a short half life relative to dosing
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-Due to phenobarbitals long half-life relative to the dosing interval there are not wide fluctuations in plasma concentrations of the drug.
-Unlike a drug like diazepam (w/ high peaks and troughs), Phenobarbital stays steady w/ very tiny peaks and troughs - How long must Phenobarbital or KBr be administered before plasma drug concentrations reach steady state?
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Phenobarbital:
-Half-life elimination is 35-75 hours (dog)
-Reaches steady state in 5-7 half-lives
-Total time = 2-3 weeks to reach steady state
KBr:
-Half-life elimination is roughly 24 days
-Reaches steady state in 4-6 months
**This is why a loading dose can be given of either drug, therefore you don’t need to wait the long time to reach the steady state** - When contemplating TDM of Phenobarbital, when would you sample if you wanted to measure peak drug concentration, trough drug concentration, during an acute manifestation of toxicity, and for a periodic recheck of the serum drug concentration?
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-Therapeutic Drug Monitoring (TDM) should be sampled 4-6 hours since last dose given to determine peak, trough, or toxicity.
-TDM should not be done until 2-3 weeks after initiation of therapy (samples can be taken early, steady state may not have been reached yet) - Describe the treatment for accidental overdosage of Phenobarbital.
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-Sodium bicarbonate to alkalinize the urine.
-Alkalinzation promotes ionization and reduces diffusability of drug
-Respiratory support when toxicity is severe enough to depress respiration
-Activated charcoal enhances body clearance - List the common side effects seen when initiating Phenobarbital therapy
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-Polyphagia
-Polydipsia
-Polyuria (due to inhibition of ADH action or release)
-Fatigue
-Listlessness
-Hepatotoxicity
-Increases in ALP and transaminase
-Hepatic hypoxia causes non-specific liver enzymes to increase following a seizures - Describe the metabolic fate of primidone in the dog, and justify the use of Phenobarbital TDM to guide therapy
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-Primidone (in vivo) is metabolized to Phenobarbital
-For TDM, you measure Phenobarbital since these levels accurately reflect the anticonvulsant and toxic effects of primidone - Explain why phenytoin is not a very useful anticonvulsant for dogs
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Phenytoin toxicity in dogs appears in two forms:
1.Dose dependent chronic hepatitis can progress to cirrhosis and appear to be reversible following drug discontinuation
2.Dose dependent intrahepatic cholestatis is accompanied by poor prognosis - List the common manifestations of bromide adverse reactions.
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-Ataxia
-Grogginess
-Sedation
-Skin reactions (in animals w/ pre-existing skin conditions)
-Vomitting
-Intermittent cough
-Radiographic changes associated w/ disease in small airways (cats) - What is the treatment of choice for status epilepticus? What route(s) of administration would you choose and why?
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Treatment of choice for status epilepticus:
-Diazepam (benzodiazepines)
Route of administration:
-IV or rectally (preferred by Erin)
-Not good orally due to low bioavailability - Why is diazepam ineffective for the long-term control of generalized seizures in dogs?
- -Tolerance to anticonvulsant activity can develop quickly, therefore long term control is not good
- List the commonly available forms of bromide.
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-Sodium
-Potassium (KBr is the most commonly used)**
-Ammonia salts - What is the emergency treatment for overdose of bromide?
- Sodium chloride
- What is the approximate half life of bromide?
- 24 days
- 5. Phenobarbital is a potent inducer of hepatic microsomal enzymes. Describe how enzyme induction will affect Phenobarbital concentrations, endogenous hormone concentrations, and the potential effectiveness and toxicity of prodrugs that require the liver
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Phenobarb concentrations:
- there will be increased clearance of the drug b/c it undergoes hepatic metabolism
Endongenous hormone concentrations:
-T4 levels decrease due to increased hepatic inactivation
-Estrogen, androgens, progesterones, and adrenocortical steroids are hydroxylated more rapidly
Phenobarb related increases in liver enzyme activity may affect other drugs by:
-Increasing the rate of biotransformation leading to therapeutic failure
-Increasing the rate of conversion of prodrugs to active compounds enhancing toxicity***
-Increasing the rate of formation of toxic metabolites increasing toxicity
-Increasing production of carcinogenic compounds by the liver increasing the risk of neoplasia