4.7 Serotonin

Question 1

Outline the production of serotonin.

Answer 1

Production:

Serotonin (5-Hydroxytryptamine) is produced by

hydroxylation and decarboxylation of tryptophan,

an essential amino acid.

Question 2

Outline the metabolism of serotonin.

Answer 2

Reuptake and inactivation by monoamine oxidase (MAo)

to produce 5-hydroxyindoleacetic acid,

which is renally excreted.

Question 3

Where is serotonin found?

Answer 3

1. • Platelets
2. • Gastrointestinal tract
     (primarily in enterochromaffin cells)
3. • Brain
     (the hypothalamus, limbic system, spinal cord, retina, and cerebellum)

Question 4

What are the types of receptors you know of

What’s their MOA

Answer 4

1. Seven families have been identified (5-HT1 through to 5-HT7).
2. Most of the receptors are coupled to G proteins
3. produce an effect via adenyl cyclase or phospholipase C.
4. The one exception is 5HT3, an ion channel.

Question 5

The effect of serotonin varies with each receptor.

Answer 5

5-HT2 receptors mediate platelet aggregation
and smooth muscle contraction..

5-HT3 receptors are concentrated in the GI tract
and the area postrema and are involved in vomiting.

5-HT6 and 7 receptors are involved in limbic function.

Question 6

What is serotonin syndrome?

Answer 6

Serotonin syndrome (SS), or serotonin toxicity,
was first described in the 1950s..

It is a spectrum of clinical findings due to excess of serotonin in the CNS.

Classical triad of symptoms
1. * Change in mental status

2. • Autonomic dysfunction
3. • Neuromuscular excitability

Question 7

What are the signs and symptoms?

Answer 7

1. • Change in mental status:
     agitation, delirium, disorientation, anxiety,
     lethargy, seizures, and hallucinations
2. • Autonomic dysfunction:
     diaphoresis, hypertension, hyperthermia,
     vomiting, tachycardia, dilated pupils, diarrhoea,
     and abdominal pain
3. • Neuromuscular changes:
     tremors, muscle rigidity,
     hyperreflexia, nystagmus
4. • Others:
     rhabdomyolysis, acute renal failure,
     disseminated intravascular
     coagulation, and circulatory failure
5. Clinical features are highly variable but usually correlate with degree of
   toxicity, and the onset can be dramatic or insidious in nature.

Question 8

How is it diagnosed?

Answer 8

The diagnosis is purely clinical.

Most validated diagnostic criteria—
Hunter Criteria—84% sensitive and 97% specific.

The Hunter Criteria for Serotonin syndrome
are fulfilled if the patient has taken a
serotonergic agent and has a
combination of one or more of the following:

• Spontaneous or inducible clonus
• Ocular clonus
• Agitation
• Diaphoresis
• Tremor
• Hyperreflexia
• Hypertonia
• Temperature > 38°C

Question 9

Hx + Exam for serotonin Sy

Answer 9

History should concentrate on
prescription and other medications,
illicit substance abuse, alternative medications,
and any recent changes to medications.

Laboratory investigations are of very little use in the diagnosis.
Serum serotonin levels do not correlate with toxicity, and other findings are generally nonspecific.

There may be an elevated white cell count and increased CK.

Question 10

Outline the principles of treatment.

Answer 10

1. • Stopping all drugs acting on serotonin
2. • Supportive care such as supplemental oxygen,
     intravenous fluids, and cardiac monitoring.
3. • Benzodiazepines for agitation and BP control
4. • Management of autonomic instability—
     can use short-acting agents such as esmolol
5. • Controlling hyperthermia

6.* Considering serotonin antagonists if available
(Cyproheptadine is the serotonin antagonist
that has been used.)

Question 11

Which drugs can precipitate the syndrome?

Answer 11

Co-administration of two serotonergic agents,

usually monoamine oxidase inhibitors (MAoI)
and selective serotonin reuptake inhibitors (SSRIs)

1. • Increased serotonin formation:
     L-tryptophan
2. • Increased serotonin release:
     Cocaine, ecstasy, amphetamines, alcohol
3. • Reduced serotonin reuptake:
     SSRIs, TCAs, pethidine, tramadol, fentanyl,
     ondansetron, St. John’s wort, etc.
4. • Inhibits serotonin metabolism:
     MAoIs, serotonin agonists, LSD
5. • Increases sensitivity of receptor:
     Lithium

Question 12

What are the anaesthetic implications?

Answer 12

1. Serotonin syndrome is uncommon but is
   often undiagnosed in milder cases.
2. Drugs that alter serotonin are given routinely
   in anaesthetic practice.
3. Patients already on one drug are being prescribed
   a second serotonergic
   agent such as alcohol, tramadol, or ondansetron.
4. Serotonin syndrome can be prevented by

• Understanding individual patient’s triggers,
  symptom patterns, and
  preferred therapies
• Continuing preventative medication
• Minimising variations in arterial blood pressure,
  temperature, and arterial CO2