A/29. Tricyclic, tetracyclic and unicyclic antidepressants. MAOinhibitors.

Question 1

Drugs need to know in this topic

Answer 1

clomipramine

amitryptiline

maprotiline

bupropion

trazodone

moclobemide

Question 2

Tricyclic antidepressants (TCA’s)

Mechanism of action

Answer 2

1. Inhibit the reuptake transporters responsible for terminating the synaptic actions of both NE and 5-HT in the CNS
2. NET (norepinephrine transporter) is responsible for norepinephrine reuptake
3. SERT (serotonin transporter) is responsible for serotonin reuptake
4. Muscarinic, α1, H1 blockade – consider side effects

Question 3

Amitriptyline

Clomipramine

Answer 3

Amitriptyline is the most potent antimuscarinic agent

Oral

1. Major depressive disorders (not 1st line)
2. Bipolar disorders
3. Acute panic attacks
4. Phobic disorders
5. Enuresis (involuntary urination)
6. Migraine (amitriptyline, imipramine)
7. Neuropathic pain disorders (diabetic neuropathy)
8. Attention deficit hyperkinetic disorder (ADHD)

Question 4

Maprotiline

Answer 4

• *1. Classified as tetracyclic antidepressant (TeCA)
  2. NET inhibition >> SERT inhibition (other properties identical to TCA’s)**

Question 5

Tricyclic, tetracyclic antidepressants

side effects

Answer 5

• *Adverse effects:**
  1. CNS depression effects → sedation, fatigue, confusion
  2. Atropine-like effects (M blockade) → dry mouth, urinary retention, constipation, blurred vision
  3. Orthostatic hypotension, ECG changes, arrhythmias (due to α1 blockade)
  4. Tremor, paraesthesia
  5. Weight gain
  6. Toxicity (‘the 3 C’s’) → coma, convulsions, cardiotoxicity (QRS and QT prolongation, Torsade)

Question 6

Tricyclic, tetracyclic antidepressants

Drug interactions

Answer 6

1. Additive CNS depression with alcohols, barbiturates, benzodiazepines, opioids
2. TCA’s may cause a reversal of the antihypertensive action of guanethidine by blocking its transport into sympathetic nerve endings
3. Hypertensive crisis with MAO inhibitors
4. Serotonin syndrome (with SSRI’s, MAO inhibitors, meperidine) → muscle rigidity, myoclonus, hyperthermia, CV instability, CNS stimulation, seizures

Question 7

MAO inhibitors

Mechanism of action

Answer 7

1. Interfere with the metabolism of amines in nerve endings, resulting in an increase in the vesicular stores of NE and 5-HT
2. MAO-A → responsible for metabolism of NE, 5-HT, tyramine
3. MAO-B → responsible for metabolism of DA, synthetic compounds

Question 8

Moclobemide

Selegiline
(MAO-B selective inhibitor)

(MAO-A selective inhibitor)

Answer 8

Oral

Antidepressant effect is achieved after 2-4 weeks

Inhibit cytochrome P450 enzymes

Major depressive disorders(Moclobemide)

Parkinsonism (adjunct to levodopa) (Selegiline)

Question 9

MAO inhibitors

Adverse effects

Answer 9

1. Insomnia
2. Hypotension
3. Sexual dysfunction
4. CNS stimulation effects → agitation, convulsions, seizures
5. Toxicity → shock, hyperthermia, seizures

Question 10

MAO inhibitors

Drug interactions:

Answer 10

1. Hypertensive crisis (with TCA’s, indirect sympathomimetics, tyramine, α1-agonists, levodopa) → elevated BP, cardiac arrhythmias, hyperthermia, excitation
2. Serotonin syndrome (with SSRI’s, TCA’s, meperidine) → muscle rigidity, myoclonus, hyperthermia, CV instability, CNS stimulation, seizures.
   *Tyramine is a naturally-occurring monoamine, metabolised by MAO-A enzymes; can be found in aged meat, cheese, and wine.
   Acts as a catecholamine-releasing agent (indirect sympathomimetic).
   Consumption of excessive dietary tyramine in the presence of a non-selective MAO inhibitor → enhanced sympathetic stimulation, potential hypertensive crisis;
   referred to as the ‘cheese effect’.
   Management with non-selective α-antagonist (Phentolamine).

Question 11

Bupropion

Answer 11

Heterocyclic antidepressants – Miscellaneous antidepressants

Inhibition of dopamine reuptake (DAT – dopamine transporter)

Oral

1. Major depressive disorders
2. Management of nicotine withdrawal

• *Adverse effects:**
  1. Dry mouth
  2. Sweating
  3. Seizures
  4. No sexual dysfunction, no weight gain
• *Contraindications:**
  1. Pre-existing seizure disorder
  2. Conditions that increase the risk of seizures(CNS tumors, CNS injury, bulimia, anorexia nervosa)

Question 12

Trazodone

Answer 12

Serotonin antagonist antidepressants

Mechanism of action:

1. Inhibition of post-synaptic 5-HT2A receptors in the CNS (post-synaptic 5-HT2A over-density is involved in the pathogenesis of depression)
2. Inhibition of serotonin reuptake (SERT)
3. With chronic use, may desensitize pre-synaptic 5-HT1A autoreceptors, thereby, increasing serotonin release (5-HT1A are inhibitory receptors)

Oral

1. Major depressive disorders
   Trazodone 2. Highly sedative (mainly used for insomnia)

• *Adverse effects:**
  1. Hepatotoxicity (nefazodone)
  2. Priapism (trazodone)
  3. Orthostatic hypotension, cardiac arrythmias – due to moderate α1 blockade activity (both agents