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CLINICAL PHARMACOKINETICS OF ANTICONVULSANT DRUGS

1. Introduction.

2. Summarised pharmacokinetic data.

3. Individual agents in brief.

4. Monitoring plasma levels.

5. Some factors influencing pharmacokinetics.

6. Conclusion.

1. Introduction:

(a) Anticonvulsant therapy was one of the first clinical areas to benefit from human pharmacokinetic studies.

(b) Studies have clearly shown that a better understanding of drug disposition (distribution, elimination) and of the variables capable of modifying it, together with an appropriate use of plasma level monitoring, leads to more effective and safer anticonvulsant therapy.

Therefore, the application of pharmacokinetic knowledge has a major role in the clinical treatment of epilepsy.

2. Summarised Pharmacokinetic Data:

The fundamental pharmacokinetic properties, and the relationship between therapeutic and toxic effects and plasma levels, have been established for most anticonvulsant drugs (see tables).

Drug	Optimum Protein Plasma Levels  (mol/L)	Binding (%)	t½ (hr)	(hr)
Carbamazapine (Tegretol)	20-40	75	15-20	12
Clonazepam (Rivotril)	0.06-0.15	80	20-60	8-12
Ethosuximide (Zarontin)	300-700	0	30-70	12
Phenobarbitone	65-170	50	50-120	12-24
Phenytoin (Dilantin)	40-80	90	8-60	12
Primidone (Mysoline)	25-70	0	6-12	12
Sodium valproate (Epilim)	300-600	90	8-15	8-12

 

3. Individual Anticonvulsants:

(a) Carbamazepine (Tegretol):

- A structural analogue of Imipramine

- Came into clinical use as an anticonvulsant in the early 1960’s - found not only to be effective, but also possessing relatively few adverse effects.

- Useful for partial and tonic-clonic seizures.

- Also used for trigeminal neuralgia, post-herpetic neuralgia and manic-depressive disorder.

- Small dosage increments initially are important to prevent toxicity (vertigo, nystagmus, drowsiness, ataxia, diplopia).

- Headache, GI upsets possible.

- Extensively metabolised: Only 2% of dose is excreted unchanged in urine.

- Elimination rate constant increases with continued exposure to the drug (auto-induction of hepatic enzymes): plasma levels fall after 2-3 weeks of therapy.

- Active epoxide metabolite (Carbamazepine - 10, 11 - Epoxide).

TABLE: Drugs That Alter Carbamazepine Plasma Concentrations
Drug	Proposed Mechanism	Clinical Comment
Phenytoin Phenobarbital Primidone	Enzyme-induction	Carbamazepine concentrations are reduced, epoxide concentrations are elevated; coadministration with more than one enzyme-inducer will result in greater reduction in carbamazepine concentration; higher dose rates and shorter dosing intervals may be required.
Propoxyphene Cimetidine  Isoniazid Erythromycin Triacetyloleanamycin	Enzyme-inhibition	Carbamazepine dose rates may need to be reduced if these drugs are given concurrently; plasma concentration monitoring is important after initiation of therapy with these drugs and after their discontinuation.
Valproic acid	Enzyme-inhibition of the epoxide	Concentrations of carbamazepine are unchanged and epoxide concentrations are elevated; reduction in dose rate is probably unnecessary.

TABLE: Effects of Carbamazepine On Other Drugs
Drug	Clinical Comments
Ethosuximide Valproic acid Clonazepam	Carbamazepine induces metabolism of these drugs; higher dose rates of these anticonvulsants and more frequent administration may be necessary.
Warfarin	Diminished effect of Warfarin (shorter prothrombin times) have been reported; the need for higher dose rates of Warfarin should be anticipated if Carbamazepine is added.
Theophylline	Lower plasma concentrations and a shorter Theophylline half-life have resulted in loss of asthma control; higher Theophylline dose rates may be required.
Doxycycline	A shorter half-life suggests lower plasma concentrations of this drug; higher dose rates may be required for adequate bacterial treatment.

 

(b) Clonazepam (Rivotril):

- Many benzodiazepines have valuable anticonvulsant properties, eg. Clobazam, Diazepam and Nitrazepam are also used to treat epilepsy.

- Clonazepam is a benzodiazepine with a dominant anti-convulsant action and is the only benzodiazepine marketed specifically as an anticonvulsant.

- Benzodiazepines reinforce the effect of GABA in opening Cl ion channels in neuronal cell membranes, leading to hyperpolarisation of the membranes.

- Drowsiness and ataxia may occur, but tend to subside with time.

- Behavioral disturbances (eg. Euphoria, aggressiveness) can occur in up to ¼ of patients.

- Tolerance develops to its anticonvulsant effects in approx 1/3 of patients after 1-6 months - accumulation within the brain of an inactive metabolite capable of competing with Clonazepam for receptor sites?

- Extensively metabolised: Less than 1% of dose is excreted unchanged in urine.

- There does not seem to be a close correlation between plasma Clonazepam levels and seizure control.

 

(c) Ethosuximide (Zarontin):

- Introduced in the mid 1950’s.

- Now a well-established and effective agent in the treatment of absences.

- Mode of action has not been established.

- Side effects uncommon and not severe (GI upsets, nausea, fatigue, dizziness).

- Rare instances of leukopaenia and pancytopaenia.

- Extensively metabolised: 20% of dose excreted unchanged in urine.

- Few drug interactions.

 

(d) Barbiturates (Phenobarbitone, Methylphenobarbitone, Primidone):

- Methylphenobarbitone and Primidone each appear to have significant anticonvulsant action in their own right.

- Effective against partial and tonic-clonic seizures.

- Sedation can be a problem (tolerance develops in most patients); nystagmus and ataxia can also occur.

- Paradoxically, may produce irritability and hyperactivity in some patients, especially children.

- Long half-lives, therefore take a long time to reach steady-state, and bd administration adequate.

- Enzyme-inducers drug interactions, eg. Warfarin, Theophylline, Oral contraceptives.

- Folate deficiency and Vitamin D deficiency (osteomalacia) possible, but relatively rare.

TABLE: Drugs That Alter Phenobarbital Serum Concentration
Drug	Proposed Mechanism	Clinical Comment
Valproic acid Chloramphenicol Cimetidine Phenytoin	Enzyme-inhibition	Phenobarbital dose rates may need to be reduced if these drugs are given concurrently. Serum concentration monitoring is necessary after starting or stopping therapy.
Ethanol	Enzyme-induction	Chronic ethanol use may increase Phenobarbital requirements.

 

TABLE: Drugs That Alter Primidone Serum Concentrations
Drug	Proposed Mechanism	Clinical Comment
Valproic acid	Enzyme-inhibition	May cause increases in both Phenobarbital and Primidone concentrations, requiring close monitoring of serum concentrations.
Isoniazid (INH)	Enzyme-inhibition	Primidone serum concentrations increase with concurrent decrease in Phenobarbital and PEMA concentrations. Careful monitoring of serum concentrations is needed when starting and stopping INH.
Phenytoin Carbamazepine	Enzyme-induction	Primidone serum concentrations are reduced, Phenobarbital concentrations are elevated. Higher dose rates and shorter dosing intervals may be required.

 

TABLE: Effect of Phenobarbital and Primidone on Serum Concentrations and Effects of Other Drugs
Drug	Clinical Comment
Doxycycline  Carbamazepine  Oral contraceptives Corticosteroids  Quinidine  Tricyclic antidepressants Chlorpromazine  Warfarin	Metabolism of these drugs is increased requiring higher dose rates to get adequate response.
Phenytoin	Concurrent use may either increase Phenytoin serum concentrations through competitive inhibition or parahydroxylation, or decrease Phenytoin serum concentrations through enzyme-induction. Close monitoring of Phenytoin concentrations is necessary.
Furosemide	Reduced renal sensitivity to the diuretic action of furosemide. The mechanism for this interaction is unknown.

 

(e) Phenytoin (Dilantin):

- Synthesised in 1908 and first tested as a possible hypnotic.

- Its anticonvulsant properties were recognised by Merritt and Putnam (1938).

- Widely used in clinical practice to treat all forms of epilepsy except absences and myoclonic seizures.

- Also occasionally used to treat trigeminal neuralgia and post-herpetic neuralgia (probably less effective than Carbamazepine), and as a cardiac antiarrythmic.

- The most extensively studied anticonvulsant.

- Extensive metabolism: main pathway is parahydroxylation to inactive HPPH.

- Michaelis-Menten (non-linear) kinetics because hydroxylation pathway is saturable.

Michaelis-Menten Kinetics:

		V . C
Rate of metabolism (R)	=	_________
		K + C

		V . C
Low C, R	~	_________			(1)
		K
	..
		V . C
Higher C, R	~	_________	=	V	(0)
		C

, 
(i) Monitoring plasma levels is vitally important.

(ii) Dosage adjustments should be small (usually 30mg/day).

Plasma Level   (mol/L)	> 200	Coma possible
	160-200	Mental changes (sedation, slurred speech).
	120-160	Ataxia
	80-120	Nystagmus
	40-80	Optimum range
	0-40	“Sub-therapeutic”

- Highly protein-bound (90%).

- Decreased binding (increased free from fraction and therefore these patients require lower than normal total plasma levels to achieve the normal therapeutic effect):-

(i) Hypoalbuminaemia, eg. 

- Liver disease
- Elderly
- Pregnancy.

(ii) Renal disease 

- Hypoalbuminaemia
- Endogenous displacers retained in plasma.

(iii) Interacting drugs, eg. 

- Warfarin
- Salicylate
- Valproate

(iv) Hyperthyroidism.

 

Therefore, ideally, free levels should be monitored.

 

- Numerous side effects: Gingival hyperplasia, acne, hirsutism, folate and Vitamin D deficiency, peripheral neuropathy, skin rashes.

 

- Many drug interactions:-

(i) Liver enzyme inducer - increased metabolism of Warfarin, Carbamazepine, Theophylline, Barbiturates, and oral contraceptives.

 

(ii) Cimetidine inhibits Phenytoin metabolism, while Carbamazepine, Barbiturates and Ethanol increase Phenytoin metabolism.

 

 

(f) Sodium valproate (Epilim):

- Very simple chemical structure, which is unlike other anticonvulsants (n-prophylpentanoic acid):-

- Synthesised in 1881.

- Its anticonvulsant properties were discovered accidentally in France in 1961, while it was being used as a solvent for testing prospective anticonvulsant drugs.

- Useful in most forms of epilepsy and often used when other drugs are found to be ineffective.

- Raises brain GABA levels by inhibiting the enzyme succinate semialdehyde dehydrogenase which catalyses the degradation of GABA.

- Extensively metabolised via a number of pathways.

- Binding decreases with:-

(i) Increasing Valproate (VPA) levels.

(ii) Renal and liver disease.

(iii) Interacting drugs; Eg. Phenytoin, Salicylate, Warfarin.

(iv) Elevated FFA.

Therefore, would be ideal to monitor free (rather than total) drug levels.

- Side effects uncommon: Nausea, vomiting, temporary hair loss, increased appetite (weight gain).

- Rarely causes severe hepatic toxicity (can be fatal) regularly monitor liver function tests and observe for abnormal bruising of jaundice.

Drug Interactions with Sodium Valproate
Drug	Mechanism	Comments
Carbamazepine, Phenytoin Phenobarbital, Primidone	Possible enzyme-induction causes increase of intrinsic clearance of VPA	Dosage increase may be required depending on patient response.
Salicylates	Displacement of VPA from binding sites leads to an increase in free fraction and clearance	Serum concentrations obtained during Salicylate co-medication may underestimate response.
Phenobarbital, Primidone	Decrease in intrinsic clearance of Phenobarbital.	Addition of VPA to Phenobarbital therapy frequently necessitates a 20%-50% decrease in Phenobarbital dose.
Phenytoin	(a) VPA displaces Phenytoin from a shared binding site on albumin, causing an increase in Phenytoin free fraction  (b) VPA is capable of inhibiting Phenytoin metabolism, causing an increase in unbound Phenytoin concentration	These two mechanisms have opposing effects on total Phenytoin concentrations and explain the observations of toxicity associated with "therapeutic" total concentrations
Ethosuximide	Possible decrease in Ethosuximide metabolism	Little effect seen in patients only on VPA and Ethosuximide, while Ethosuximide concentrations may increase in patients on multiple antiepileptic drug therapy.

 

4. Monitoring Plasma Levels of Anticonvulsant Drugs:

Why?

- Large pharmacokinetic variability.

- Low therapeutic indices.

- Clinical effect not easily quantifiable (Eg. Hypoglycaemics, hypotensives, anticoagulants).

- Generally good correlations between plasma levels and therapeutic effect.

- Saturable metabolism with Phenytoin.

- Drug interactions common.

When?

- Initiation of therapy or dosage change (NB: Wait for steady-state).

- Poor seizure control.

- Appearance of toxic symptoms.

- Addition of withdrawal of other drugs (possible interactions).

- Pregnancy (monthly).

- Routine check on compliance (6 monthly if well controlled).

 

5. Some Factors That Influence Anticonvulsant Pharmacokinetics:

(a) Drug interactions (numerous):

(i) Anticonvulsant/anticonvulsant:

Eg. Carbamazepine and Phenobarbitone increase Phenytoin metabolism.

Valproic acid reduces Phenobarbitone metabolism.

(ii) Anticonvulsant/other drug:

Eg. Cimetidine decreases metabolism of most anticonvulsants.

Clinical implications:

- Avoid polytherapy.

- Carefully monitor plasma levels if receiving multiple drugs.

(b) Age:

- Neonates:

- Immature metabolic pathways.

- Infants/children (2 months - 7 years):

- Elimination greater than adults + t½

- Need higher dose (mg/kg).

- Elderly:

- Metabolism may be reduced.

- Hypoalbuminaemia - protein binding.

Clinical implications:

Carefully monitor plasma anticonvulsant levels in the young and elderly (free levels preferable).

(c) Diseases:

(i) Liver disease (low hepatic extraction ratio drugs):

- Hypoalbuminaemia (protein binding).

- metabolism in chronic diseases (eg. Cirrhosis).

(ii) Renal disease:

- Most anticonvulsants are primarily eliminated by metabolism (eg. dosage reduction of Phenobarbitone required only in severe renal disease).

- Protein binding (no dosage reduction as total clearance) - care when interpreting total levels.

Implications:

Plasma anticonvulsant levels should be carefully monitored in patients with these diseases. Ideally, free levels should be measured with Phenytoin and Valproate.

 

6. Conclusion:

Monitoring plasma levels of anticonvulsants and the application of pharmacokinetic knowledge, by individualising anticonvulsant drug regimens, have important roles in the effective treatment of epileptic patients.