A/31. Norepinephrine and serotonin receptor antagonist antidepressants. Agomelatine. Tianeptine. Agents used for treatment of manic phase of bipolar disorders.

Question 1

Drugs need to know in this topic

Answer 1

mirtazapine agomelatine lithium carbamazepine valproate

Question 2

Lithium

Mechanism of action

Answer 2

1. Inhibits inositol monophosphatase enzyme → prevents recycling of inositol
2. Decreased synthesis of inositol triphosphate (IP3) and diacylglycerol (DAG) → interfere with the action of Gq-coupled receptors
3. Decreased cAMP levels → interfere with the action of Gs-coupled receptors

Question 3

Lithium

Pharmacokinetic properties

Drug interactions

Answer 3

1. Oral
2. Not metabolised, excreted unchanged in urine
3. T1/2 20 h’
4. Narrow therapeutic index; requires monitoring of plasma levels to establish effective and safe dosage regimen
5. Increased plasma levels (risk for enhanced toxicity) → dehydration, NSAID’s, ACE inhibitors, thiazide diuretics (chronic use), loop diuretics (chronic use)
6. Increased renal clearance (plasma levels decreased) → caffeine, theophylline

Question 4

Lithium

Clinical use

Adverse effects and toxicity

Answer 4

1. Acute treatment of bipolar disorders (manic-depressive diseases)
2. Maintenance therapy – decrease frequency and magnitude of mood swings (‘mood stabilizer’)
   #Antipsychotic and/or benzodiazepines are usually required at the beginning of treatment, due to the slow onset of action of lithium
   ##Antidepressant drugs are often used concomitantly during maintenance therapy

Adverse effects and toxicity
1. Flu-like symptoms
2. GI distress (nausea, vomiting, diarrhea)
3. Neurotoxicity: tremors, seizures, ataxia, aphasia, sedation
4. Hypothyroidism and goiter (TSH act via Gs-coupled receptor, lithium as peripheral deiodinase inhibitor)
5. Nephrogenic diabetes insipidus, usually reversible (renal ADH act via Gs-coupled receptors)
6. Acute toxicity → nausea, vomiting, slurred speech, hyperreflexia, ataxia, seizures; treat by discontinuing agent, aggressive hydration, consider
haemodialysis
7. Teratogenicity → Ebstein’s anomaly (malformed tricuspid valve, small RV, enlarged RA, tricuspid regurgitation, cardiac arrhythmias)

Question 5

Mirtazapine

Answer 5

Heterocyclic antidepressants

Oral

Major depressive disorders

• *Mechanism of action:**
  1. α2 selective antagonist
  2. Pre-synaptic α2 receptors are inhibitory (involved in feedback inhibition) → inhibition results in increased amine release from nerve terminals
  3. 5-HT2, 5-HT3, H1 receptor inhibition
• *Adverse effects:**
  1. Weight gain
  2. Sedation (due to H1 blockade)

Question 6

Agomelatine

Answer 6

Oral

Major depressive disorders

• *Mechanism of action:**
  1. Agonist at MT1 and MT2 receptors in the suprachiasmatic nucleus (melatonin receptors)
  2. 5-HT2, 5-HT3 receptor inhibition
• *Adverse effects:**
  1. Weight gain

Question 7

Valproic acid

MOA

Answer 7

1. Inhibits T-type Ca2+ channels (in thalamic neurons)
2. Inhibits neuronal Na+ channels
3. Facilitates the inhibitory effects of GABA (inhibits GABA transaminase)
4. Increases neuronal K+ permeability (excitation ↓)

Question 8

Valproic acid

Characteristics

Indications

side effects

Answer 8

Oral

Hepatic P450 metabolism

Inhibitor of cytochrome P450
enzymes

1. Seizures (broad-spectrum; including absence seizures)
2. Bipolar disorders
3. Migraine

• *Side effects:**
  1. GI distress (nausea, vomiting, abdominal pain)
  2. Hepatotoxicity
  3. Thrombocytopenia – requires monitoring of PLT count
  4. Pancreatitis
  5. Alopecia
  6. Weight gain
  7. Teratogenicity → neural tube defects (spina bifida)

Question 9

Carbamazepine

MOA

Answer 9

Narrowspectrum

Inhibition of axonal Na+ channels
Prevent seizure propagation, but not initiation

Question 10

Carbamazepine

Characteristics

Indications

side effects

Answer 10

1. Oral (well absorbed)
2. Hepatic P450 metabolism
3. Inducer of cytochrome P450 enzymes, including enzymes responsible for its own metabolism
4. Tonic-clonic (generalized) seizures
5. Partial seizures
6. Trigeminal neuralgia (1st-line)
7. Bipolar disorders

Side effects:
1. CNS depression (dose-dependent), ataxia
2. Diplopia
3. Stevens-Johnson syndrome (exfoliative dermatitis)
4. ADH secretion ↑ (SIADH - dilutional hyponatremia)
Osteomalacia
5. Megaloblastic anemia
6. Aplastic anemia
7. Teratogenicity → neural tube defects (spina bifida),
craniofacial anomalies