Haematology and immunology: Pharmacology - Histamine, serotonin and ergot alkaloids Flashcards
What are autocoids?
Biologically active amines with complex physiologic and pathologic effects, usually released locally with a brief duration of action
Four subtypes of autocoids
Amines (e.g. histamine, serotonin)
Endogenous peptides (e.g. vasopressin, angiotensin)
Prostaglandins and leukotrienes
Cytokines
Where is histamine found and what are its actions at each site?
Within mast cells (bound in granules): inflammatory response
Brain: functions as neurotransmitter
Enterochromaffin-like (ECL) cells: gastric acid secretagogue (activates parietal cells)
Histamine receptor subtypes, distribution and effects
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)
Two nervous system effects of histamine
- Pain and itch (via activation of sensory nerve endings)
- Appetite and satiety
Two CV system effects of histamine
- Vasodilation (decreased BP, flushing, warmth)
- Reflex tachycardia
Effects of histamine on bronchiolar smooth muscle. Which receptor mediates this response?
Bronchoconstriction
Mediated by H1 receptors
Effects of histamine on GI smooth muscle. Which receptor mediates this response?
Increased gastric motility (large doses can cause diarrhoea)
Mediated by H1 receptors
Effects of histamine on GI secretory tissue. Which receptor mediates this response?
Stimulates gastric acid secretion (and to lesser extent pepsin and IF) in stomach, and secretions in small and large intestine
Mediated by H2 receptors
Which histamine receptor is primarily involved in the triple response”
H1
What is the difference between first and second generation H1 antagonists?
First gen: more sedating, more likely to block autonomic receptors
Second gen: less sedating (reduced CNS distribution)
Absorption, time to peak concentration, and duration of action of H1 antagonists
Rapidly absorbed
Peak concentration within 1-2hrs
Duration 4-6hrs typically (some second-gen longer-acting 12-24hrs)
Two examples of first gen H1 antagonists
Cyclizine
Promethazine
Three examples of second gen H1 antagonists
Fexofenadine
Loratadine
Cetirizine
Describe seven classes of actions of H1 antagonists
First gen H1 antagonists in particular may cause blockade of receptors other than histamine, including muscarinic cholinoceptor, a-adrenoceptor, serotonin and local anaesthetic sites
- Sedation
- Antiemetic
- Antiparkinsonism effects: some H1 antagonists can be used to treat antipsychotic-induced EPSEs
- Antimuscarinic: may cause urinary retention, blurred vision
- Adrenoceptor-blocking: may cause orthostatic hypotension
- Serotonin-blocking
- Local anaesthesia: block Na+ channels in excitable membranes
Three examples of H2 antagonists
Cimetidine
Ranitidine
Nizatidine
What are H2 antagonists used to treat?
GORD
PUD (although largely superseded by PPI)
Briefly describe the synthesis, storage and transport of serotonin
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)
Where is serotonin found in humans?
Enterochromaffin cells in GI tract (>90% of 5HT found here)
Platelets
Neurons (including raphe nuclei of brainstem, enteric nervous system, and around blood vessels)
What is serotonin the precursor to? Where is this synthesised?
Melatonin (synthesised in pineal gland)
Describe the effects of serotonin on the nervous system, respiratory system, CV system, GI tract, skeletal muscle, and eye
- Nervous system: role in mood, sleep, appetite, temperature regulation, pain perception, BP regulation, vomiting
- Respiratory system: bronchoconstriction
- CV system: venoconstriction, vasoconstriction except in skeletal muscle and heart, vasodilation in heart, platelet aggregation
- GI tract: increased GI motility
- Skeletal muscle: vasodilation
- Eye: reduced IOP
Which serotonin receptors are involved in the vomiting reflex? Where are these located?
5HT-3 receptors in GI tract and vomiting centre of medulla
List 13 drugs which may precipitate serotonin syndrome
- SSRIs
- Second-generation antidepressants (e.g. venlafaxine)
- MAOIs
- Linezolid
- Tramadol
- Pethidine
- Fentanyl
- Ondansetron
- Sumatriptan
- MDMA
- LSD
- St John’s wort
- Ginseng
Clinical presentation of serotonin syndrome
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)
What is the cause of serotonin syndrome?
Excess synaptic serotonin -> excess serotonergic CNS activity
Usually due to overdose of single drug or concurrent use of several drugs
How is serotonin syndrome managed?
Supportive management:
- Sedation (BZD)
- Paralysis, intubation and ventilation
Can consider 5HT2 block with cyproheptadine or chlorpromazine
What class of medication are the triptans?
5HT1 agonists
In what group of patients are triptans contraindicated and why?
Patients with or at risk of coronary artery disease
Can cause coronary artery vasospasm
What are triptans used for? What is their proposed mechanism of action?
First-line for acute severe migraine
Inhibit vasodilation causing perivascular oedema and activation of pain nerve endings in dura
What are carcinoid tumours? What syndrome do they produce?
GI neuroendocrine malignancies, most commonly occurring in the terminal ileum and appendix
Produce serotonin, histamine, bradykinin, and/or prostaglandins to cause carcinoid syndrome
Four symptoms of carcinoid syndrome
- Diarrhea
- Facial flushing
- Bronchospasm
- Hypotension and vasodilatory shock
How might carcinoid tumour be diagnosed?
24 hour urinary 5-HIAA (serotonin metabolite)
Mechanism of action and clinical uses of cyproheptadine
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)
Mechanism of action of ondansetron
5HT-3 receptor antagonist
Four receptors found in high concentration in the vomiting centre of the medulla
- Muscarinic
- H1
- 5HT3
- Neurokinin-1 (NK1)
Four sources of afferent input to medullary vomiting centre
- Chemoreceptor trigger zone (area postrema; located outside BBB)
- Vestibular system
- Vagal and spinal afferent nerves from GIT
- CNS
Where is the vomiting centre located?
NTS in the medulla
Pharmacokinetics of ondansetron
Absorption and metabolism: extensive hepatic metabolism, half-life 4-9hrs
Elimination: renal and hepatic (dose-reduction in hepatic insufficiency)
Three symptoms of ergot toxicity
Hallucinations
Prolonged vasospasm (may cause gangrene)
Stimulation of uterine smooth muscle (may result in abortion during pregnancy)
Which three receptor types do ergot alkaloids act on?
a-adrenoceptors
Dopamine receptors
5HT receptors
Four examples of ergot alkaloid drugs and their uses
- LSD: recreational use
- Bromocriptine: hyperprolactinaemia
- Ergotamine: migraine
- Ergonovine: PPH
Effects of ergot alkaloids on the CNS, vascular smooth muscle, uterine smooth muscle, and GIT
- CNS: hallucinogenic, suppression of PLN secretion through activation of regulatory dopamine receptors
- Vascular smooth muscle: prolonged vasospasm
- Uterine smooth muscle: stimulates contraction
- GIT: increased motility (nausea, vomiting and diarrhoea)
What is scombroid poisoning? How is it treated?
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)
