Glossary of Grimm Anti-convulsants

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Definition of Primary Seizure
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
-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?
-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

-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?
-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.
-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
-Polyuria (due to inhibition of ADH action or release)
-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
-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
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.
-Skin reactions (in animals w/ pre-existing skin conditions)
-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?
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.
-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
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

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