Lecture 20: Pharmacokinetics of CNS drugs

Question 1

What are the rationales for analysing drug concentrations?

Answer 1

• identify patients with unusual pharmacokinetics (fast/slow metaboliser)
• establish an individual therapeutic concentration
• aid diagnosis of clinical toxicity
• to assess compliance, especially if seizures are uncontrolled or response changes
• to guide dosage adjustment in “special populations” e.g. patients with comorbidities, pregnancy, children
• when an interacting drug is added or removed
• when the drug has dose‐dependent (non-linear) pharmacokinetics (phenytoin)

Question 2

What are the characteristics of anti epileptic drugs?

Answer 2

• Carbamazepine: Hepatic metabolism CYP3A4, auto-induction, active metabolite, many drug interactions, inducer
• Phenobarbital:
  Hepatic metabolism CYP2C9, CYP 2C19, CYP2E1, many drug interactions, inducer
• Phenytoin
  Hepatic metabolism CYP2C9 (80%), CYP2C19, nonlinear elimination, many drug interactions, inducer
• Valproic acid
  Hepatic metabolism, glucoronidation, CYP2C9, CYP2A6, nonlinear protein binding, many drug interactions, inhibitor
• Levetiracetam
  30% metabolised by blood esterase, 70% renal elimination, concentrations reduced by old, inducing AEDs
• Lamotrigine
  Hepatic metabolism (mainly UGT1A4) to glucuronide conjugates, many drug interactions
• Topiramate
  Hepatic metabolism (50%) isoenzymes unknown, many drug interactions

Question 3

What is an enzyme inducer?

Answer 3

A type of drug that increases the metabolic activity of an enzyme either by binding to the enzyme and activating it, or by increasing the expression of the gene coding for the enzyme.

Question 4

How are most antipsychotics eliminated?

Answer 4

By hepatic metabolism

Question 5

What is the indication for lithium? Mode of action? Monitoring required Side effects? Toxicity? Drug interactions? ADME?

Answer 5

Indication:
- Prophylaxis/ treatment of mania and depression

Mode of action:
- Unknown - enhances seratonin, norepinephrine, glutamatergic, protein kinase C activity, influences second messenger systems, may stimulate neurogenesis

Monitoring:
- Baseline renal, cardiac and thyroid function then every 6 monthly
- Measure Li+ concentration weekly till stable then every 3 months for 1 year then 6 monthly, 3 monthly if high risk

Side effects:
- Hypothyroidism, rarely hyperthyroidism
- Weight gain
- Hypercholesterolaemia
- Hyperparathyroidism and hypercalcaemia
- Nephrogenic diabetes insipidus (lithium competes with ADH receptors in the kidney) and dehydration
- Permanent kidney damage (rare)

Overdose and toxicity
- >1-1.2mmol/L in elderly: tremor, nausea, diarrhoea, drowsiness, confusion, apathy, restfulness, diabetes insipidus

• > 1.5 mmol/L: GIT, CNS, kidney, endocrine, cardiovascular, haematological, muscle, dermatological, opthalomogical
• > 2 mmol/L potentially life-threatening toxicity : muscle twitching, convuslions, renal failure, dehydration, electryolye imbalane, coma , death

Drug interactions:
- Thiazide diuretics; inhibit Na reabsoprtion in distal tubule, compensatory increase reabsoprtion of lithium in proximal tubule
- Loop diuretics: conflicting data, case reports of major toxicity esp in elderly
- NSAIDs: Inhibit prostaglandin synthesis by blocking COX 1 and COX 2, reduce renal blood flow, increase reabsoprtion of Na and Li
- ACE inhibitor and ARBs: decrease Na reabsorption, reduce GFR - compensatory increase in lithium reabsorption in proximal tubule
- Large doses of sodium bicarbonate antacids reduce Li+ concentrations
- Alcohol: avoid if possible but may use may be linked with condition so difficult to control

Absorption:
- Adminstered as a salt of lithium carbonate (tablets) or lithium citrate (liquid)
- Absorbed by passive diffusion as lithium ion
- Bioavailability 60-90% with modified release formulations
- Peak concentrations 5-6 hours after modified release, 1 – 2 hour after immediate release formulation

Elimination