Haematology and immunology: Pharmacology - Histamine, serotonin and ergot alkaloids

Question 1

What are autocoids?

Answer 1

Biologically active amines with complex physiologic and pathologic effects, usually released locally with a brief duration of action

Question 2

Four subtypes of autocoids

Answer 2

Amines (e.g. histamine, serotonin)
Endogenous peptides (e.g. vasopressin, angiotensin)
Prostaglandins and leukotrienes
Cytokines

Question 3

Where is histamine found and what are its actions at each site?

Answer 3

Within mast cells (bound in granules): inflammatory response
Brain: functions as neurotransmitter
Enterochromaffin-like (ECL) cells: gastric acid secretagogue (activates parietal cells)

Question 4

Histamine receptor subtypes, distribution and effects

Answer 4

H1: smooth muscle, endothelium, brain (role in allergy, asthma, increased GI motility)
H2: gastric mucosa, cardiac muscle, mast cells, brain (role in gastric acid secretion)
H3: presynaptic autoreceptors and heteroreceptors; brain, myenteric plexus, other neurons (may play role in satiety)
H4: eosinophils, neutrophils, CD4 T cells (role in chemotaxis and cytokine production)

Question 5

Two nervous system effects of histamine

Answer 5

1. Pain and itch (via activation of sensory nerve endings)
2. Appetite and satiety

Question 6

Two CV system effects of histamine

Answer 6

1. Vasodilation (decreased BP, flushing, warmth)
2. Reflex tachycardia

Question 7

Effects of histamine on bronchiolar smooth muscle. Which receptor mediates this response?

Answer 7

Bronchoconstriction
Mediated by H1 receptors

Question 8

Effects of histamine on GI smooth muscle. Which receptor mediates this response?

Answer 8

Increased gastric motility (large doses can cause diarrhoea)
Mediated by H1 receptors

Question 9

Effects of histamine on GI secretory tissue. Which receptor mediates this response?

Answer 9

Stimulates gastric acid secretion (and to lesser extent pepsin and IF) in stomach, and secretions in small and large intestine
Mediated by H2 receptors

Question 10

Which histamine receptor is primarily involved in the triple response”

Answer 10

H1

Question 11

What is the difference between first and second generation H1 antagonists?

Answer 11

First gen: more sedating, more likely to block autonomic receptors
Second gen: less sedating (reduced CNS distribution)

Question 12

Absorption, time to peak concentration, and duration of action of H1 antagonists

Answer 12

Rapidly absorbed
Peak concentration within 1-2hrs
Duration 4-6hrs typically (some second-gen longer-acting 12-24hrs)

Question 13

Two examples of first gen H1 antagonists

Answer 13

Cyclizine
Promethazine

Question 14

Three examples of second gen H1 antagonists

Answer 14

Fexofenadine
Loratadine
Cetirizine

Question 15

Describe seven classes of actions of H1 antagonists

Answer 15

First gen H1 antagonists in particular may cause blockade of receptors other than histamine, including muscarinic cholinoceptor, a-adrenoceptor, serotonin and local anaesthetic sites

1. Sedation
2. Antiemetic
3. Antiparkinsonism effects: some H1 antagonists can be used to treat antipsychotic-induced EPSEs
4. Antimuscarinic: may cause urinary retention, blurred vision
5. Adrenoceptor-blocking: may cause orthostatic hypotension
6. Serotonin-blocking
7. Local anaesthesia: block Na+ channels in excitable membranes

Question 16

Three examples of H2 antagonists

Answer 16

Cimetidine
Ranitidine
Nizatidine

Question 17

What are H2 antagonists used to treat?

Answer 17

GORD
PUD (although largely superseded by PPI)

Question 18

Briefly describe the synthesis, storage and transport of serotonin

Answer 18

Synthesised from L-tryptophan
Stored in vesicles or rapidly inactivated by MAO
Transported into platelets or nerve endings by active serotonin transport mechanism (SERT) and concentrated in vesicles by vesicle-associated transport (VAT)

Question 19

Where is serotonin found in humans?

Answer 19

Enterochromaffin cells in GI tract (>90% of 5HT found here)
Platelets
Neurons (including raphe nuclei of brainstem, enteric nervous system, and around blood vessels)

Question 20

What is serotonin the precursor to? Where is this synthesised?

Answer 20

Melatonin (synthesised in pineal gland)

Question 21

Describe the effects of serotonin on the nervous system, respiratory system, CV system, GI tract, skeletal muscle, and eye

Answer 21

1. Nervous system: role in mood, sleep, appetite, temperature regulation, pain perception, BP regulation, vomiting
2. Respiratory system: bronchoconstriction
3. CV system: venoconstriction, vasoconstriction except in skeletal muscle and heart, vasodilation in heart, platelet aggregation
4. GI tract: increased GI motility
5. Skeletal muscle: vasodilation
6. Eye: reduced IOP

Question 22

Which serotonin receptors are involved in the vomiting reflex? Where are these located?

Answer 22

5HT-3 receptors in GI tract and vomiting centre of medulla

Question 23

List 13 drugs which may precipitate serotonin syndrome

Answer 23

1. SSRIs
2. Second-generation antidepressants (e.g. venlafaxine)
3. MAOIs
4. Linezolid
5. Tramadol
6. Pethidine
7. Fentanyl
8. Ondansetron
9. Sumatriptan
10. MDMA
11. LSD
12. St John’s wort
13. Ginseng

Question 24

Clinical presentation of serotonin syndrome

Answer 24

Onset within hours of drug administration, with symptoms including:
Shivering (tremor)
Hyperreflexia, myoclonus
Increased temperature
Vital sign instability (HTN)
Encephalopathy (agitation, coma)
Restlessness
Sweating

Also get hyperactive bowel sounds and diarrhoea (increased GI motility)

Question 25

What is the cause of serotonin syndrome?

Answer 25

Excess synaptic serotonin -> excess serotonergic CNS activity Usually due to overdose of single drug or concurrent use of several drugs

Question 26

How is serotonin syndrome managed?

Answer 26

Supportive management: - Sedation (BZD) - Paralysis, intubation and ventilation Can consider 5HT2 block with cyproheptadine or chlorpromazine

Question 27

What class of medication are the triptans?

Answer 27

5HT1 agonists

Question 28

In what group of patients are triptans contraindicated and why?

Answer 28

Patients with or at risk of coronary artery disease Can cause coronary artery vasospasm

Question 29

What are triptans used for? What is their proposed mechanism of action?

Answer 29

First-line for acute severe migraine Inhibit vasodilation causing perivascular oedema and activation of pain nerve endings in dura

Question 30

What are carcinoid tumours? What syndrome do they produce?

Answer 30

GI neuroendocrine malignancies, most commonly occurring in the terminal ileum and appendix Produce serotonin, histamine, bradykinin, and/or prostaglandins to cause carcinoid syndrome

Question 31

Four symptoms of carcinoid syndrome

Answer 31

1. Diarrhea 2. Facial flushing 3. Bronchospasm 4. Hypotension and vasodilatory shock

Question 32

How might carcinoid tumour be diagnosed?

Answer 32

24 hour urinary 5-HIAA (serotonin metabolite)

Question 33

Mechanism of action and clinical uses of cyproheptadine

Answer 33

H1 and 5HT2 receptor antagonist Used to treat smooth muscle manifestions of carcinoid tumour, and in cold-induced urticaria, may also be used in serotonin syndrome (but only available orally)

Question 34

Mechanism of action of ondansetron

Answer 34

5HT-3 receptor antagonist

Question 35

Four receptors found in high concentration in the vomiting centre of the medulla

Answer 35

1. Muscarinic 2. H1 3. 5HT3 4. Neurokinin-1 (NK1)

Question 36

Four sources of afferent input to medullary vomiting centre

Answer 36

1. Chemoreceptor trigger zone (area postrema; located outside BBB) 2. Vestibular system 3. Vagal and spinal afferent nerves from GIT 4. CNS

Question 37

Where is the vomiting centre located?

Answer 37

NTS in the medulla

Question 38

Pharmacokinetics of ondansetron

Answer 38

Absorption and metabolism: extensive hepatic metabolism, half-life 4-9hrs Elimination: renal and hepatic (dose-reduction in hepatic insufficiency)

Question 39

Three symptoms of ergot toxicity

Answer 39

Hallucinations Prolonged vasospasm (may cause gangrene) Stimulation of uterine smooth muscle (may result in abortion during pregnancy)

Question 40

Which three receptor types do ergot alkaloids act on?

Answer 40

a-adrenoceptors Dopamine receptors 5HT receptors

Question 41

Four examples of ergot alkaloid drugs and their uses

Answer 41

1. LSD: recreational use 2. Bromocriptine: hyperprolactinaemia 3. Ergotamine: migraine 4. Ergonovine: PPH

Question 42

Effects of ergot alkaloids on the CNS, vascular smooth muscle, uterine smooth muscle, and GIT

Answer 42

1. CNS: hallucinogenic, suppression of PLN secretion through activation of regulatory dopamine receptors 2. Vascular smooth muscle: prolonged vasospasm 3. Uterine smooth muscle: stimulates contraction 4. GIT: increased motility (nausea, vomiting and diarrhoea)

Question 43

What is scombroid poisoning? How is it treated?

Answer 43

Histamine toxicity caused by ingesting fish contaminated with large quantities of histamine due to improper preservation (bacteria converts histidine to histamine Treated with histamine antagonists (especially H1)