Tiêu đề 11. TDM OF DRUGS USED FOR SEIZURE DISORDERS.pdf ✅

PHARMD GURU Page 1 THERAPEUTIC DRUG MONITORING OF VALPROIC ACID: GENERAL INTRODUCTION:  Valproic acid is an anti-convulsant, which is used to treat seizures.  It affects chemicals in the body that may be involved in causing seizures.  Sometimes used in combination with other drugs. USES:  Valproic acid is used to treat various types of seizure disorders. Valproic acid is sometimes used together with other seizure medications.  Valproic acid is also used to treat manic episodes related to bipolar disorder (manic depression), and to prevent migraine headaches. MECHANISM OF ACTION:  Valproic acid causes increased availability of GABA, an inhibitory neurotransmitter, to brain neurons.  It may also enhance the action of GABA or mimic its action at postsynaptic receptor sites.  Valproic acid also blocks voltage dependent sodium channels, which results in the suppression of high-frequency repetitive neuronal firing. PHARMACOKINETIC PROFILE: ABSORPTION: Absorption and Bioavailability:  Rapidly and completely absorbed (f = 1).  Oral (fasting) Peak: 1-3 hours.  Meal (food) peak late 6-8 hours.  Enteric coated absorbed delayed 3-5 hrs (lag time 2-4 hrs). DISTRIBUTION: Distribution and Protein binding: Vd = 0.15 L/Kg (0.1 - 0.5 L/Kg) Protein (Albumin) binding get saturated at a concentration >50 μg/ml TDM OF DRUGS USED FOR SEIZURE DISORDERS
PHARMD GURU Page 2 METABOLISM: >95% hepatic metabolism. EXCRETION:  1-3% renal excretion.  Oral clearance (Cl/F) is 7-12 ml/h/kg for adults.  In children 6-12 years old, oral clearance) 10-20 ml/h/kg. HALF-LIFE (t1/2):  Half-life is 12-18 hours in adults.  Half-life for children 6-12 year old is 6-8 hours. ADR/TOXIC EFFECT: Adverse effect related to plasma drug concentration: PLASMA LEVEL SYMPTOMS >75 mcg/L Ataxia, sedation, lethargy. >100 mcg/L Tremors. >175 mcg/L COMA, stupor. DRUG INTERACTIONS:  Phenytoin, lamotrigine, rifampin, and carbamazepine can increase valproic acid clearance and decrease valproic acid steady-state serum concentrations.  Cimetidine, chlorpromazine, and felbamate are examples of drugs that decrease valproic acid clearance and increase valproic acid steady-state concentrations. THERAPEUTIC RANGE: Dose: 50 – 100 μg/ml  Generalized seizures: 30 – 60 μg/ml  Partial seizures: 55 – 100 μg/ml TOXIC RANGE: > 100 μg/ml
PHARMD GURU Page 3 CONTRAINDICATIONS:  Contraindicated in:  Liver disease.  Urea cycle disorders.  Known porphriya.  Pregnancy. MONITORING PARAMETERS:  The goal of therapy with anticonvulsants is to reduce seizure frequency and maximize quality of life with a minimum of adverse drug effects.  Patients should be monitored for concentration-related side effects (ataxia, sedation, lethargy, tiredness, tremor, stupor, coma, and thrombocytopenia) as well as gastrointestinal upset associated with local irritation of gastric mucosa (nausea, vomiting, and anorexia).  Elevated liver function tests, increased serum ammonia, alopecia, and weight gain have been reported during chronic Valproic acid treatment.  Serious, but rare, idiosyncratic side effects include hepatotoxicity, pancreatitis, pitting edema, systemic lupus-like reactions, and leucopenia with bone marrow changes. DOSAGE ADJUSTMENTS:  For renal impairment: No adjustment is necessary, protein binding is reduced and may lead to inaccurate measurement of total valproate concentrations.  For Hepatic impairment: It is not recommended. It is contraindicated. SAMPLING TIME:  3-5 days may be required to reach the steady state concentration.  Trough samples are taken, but sometimes both trough and peak samples are withdrawn. ASSAYS USED:  Immunoassays.  HPLC.
PHARMD GURU Page 4 ADDITIONAL INFORMATION TDM OF CARBAMAZEPINE: INTRODUCTION:  Carbamazepine is an iminostilbene derivative related to the tricyclic antidepressants.  It used in the treatment of tonic-clonic (grand mal), partial or secondarily generalized seizures.  Carbamazepine is also a useful agent to treat trigeminal neuralgia and bipolar affective disorders.  The drug is used primarily as a prophylactic agent in the chronic therapy of epilepsy. NEED OF TDM: The accepted therapeutic range for Carbamazepine is 4-12 μg/ml when the drug is used for the treatment of seizures. 1) Carbamazepine plasma protein binding is quite variable among individuals because it is bound to both albumin and α1-acid glycoprotein (AGP). In patients with normal concentrations of these proteins, plasma protein binding is 75-80% resulting in a free fraction of drug of 20-25%. AGP secreted in large amount in diseases like trauma, heart failure, myocardial infarction.