Histamine and Serotonin Pharmacology (Week 1--Melega) Flashcards
Enterochromaffin-like cells (ECL cells)
In gastric mucosa (stomach)
Synthesize, store and release histamine
What stimulates ECL cells to secrete histamine?
Gastrin binding to CCK2 receptor on ECL cell
ACh binding to muscarinic receptor on ECL cell
What causes parietal cells to secrete acid?
1) ACh
2) Gastrin on CCK2 receptors
3) Histamine on H2 receptors (remember, histamine secretion itself is also stimulated by ACh and gastrin)
What mechanism do ACh, gastrin and histamine use to cause H+ secretion from parietal cells?
1) ACh –> Ca2+ increase
2) Gastrin –> Ca2+ increase
3) Histamine –> G-coupled protein –> cAMP
What can inhibit H+ secretion by parietal cells?
Prostaglandins –> EP3 receptor –> inhibit cAMP
What is an antacid?
Antacids neutralize H+ in the stomach by reacting with H+ to create water
Ex: aluminum hydroxide, magnesium hydroxide: OH- + H+ –> H2O
Ex: sodium bicarbonate: HCO3- + H+ –> H2CO3 –> H2O + CO2
What is an H2 antagonist?
H2 antagonists block H+ secretion by parietal cells into the stomach
Reversibly inhibit histamine binding to H2 receptors (competitive inhibitors)
Ex: Cimetidine, ranitidine, famotidine, nizatidine
What is a proton pump inhibitor (PPI)?
Irreversibly binds and inactivates H/K ATPase in parietal cells to inhibit H+ secretion into the stomach
Most potent gastric-acid suppressing agents (decrease secretion by 90% or more), and have limited side effects because concentration much higher in secretory canaliculus of parietal cell than in the rest of the body
Ex: omeprazole, esomeprazole
What do prostaglandins do in the GI tract?
1) Prostaglandins bind EP3 on parietal cell and inhibit cAMP so H/K ATPase can’t secrete H+
2) Prostaglandins bind EP3 to stimulate mucus and HCO3- secretion from surface mucous cells
What is the effect of NSAIDs on the GI tract?
NSAIDs (aspirin) are COX inhibitors, so block production of prostaglandins –> parietal cells can secrete more H+ and surface mucous cells can’t secrete mucus –> erosion of epithelial cells –> GI bleeding or ulcers
What is the function of mucus?
Protect the mucosa from endogenous “aggressors” acid and pepsin
Mucus provides stable layer to neutralize acid with bicarb and is a permeability barrier to luminal pepsin
What is serotonin and where is it found?
5-hydroxytryptamine
In blood (platelets), gut (EC cells) and neurons (cells in raphe nucleus)
What type of receptors are there for serotonin?
Almost all are G-protein coupled receptors (5-HT1P, 5-HT4)
5-HT3 is a ligand gated Na+ ion channel
Where does serotonin in our body come from?
Synthesis from tryptophan, not from diet (serotonin we eat is polar and charged and gets metabolized in gut wall and liver before entering blood)
How is serotonin synthesized then metabolized?
Tryptophan –> (tryptophan hydroxylase) –> 5-hydroxytryptophan –> (aromatic amino acid decarboxylase) –> serotonin
Serotonin –> (MAO and aldehyde dehydrogenase) –> 5-HIAA (into circulation then eliminated in urine)
How is most of serotonin cleared?
SERT: serotonin reuptake transporter
EC cells do not have SERT, but enterocytes (epithelial cells of GI tract) do, and they uptake serotonin and metabolize it (then secrete 5-HIAA in urine)
Enterochromaffin (EC) cells
Throughout GI tract, are major source of intestinal serotonin
Note: EC cells and 5-HT interneurons contain 95% of body’s 5-HT
How does the CNS know what is going on in the gut?
Serotonin activates extrinsic primary afferent neurons
EC cells are sensory cells of the gut that give info to the CNS
Mechanical (pressure) or chemical signals in intestinal lumen –> apical tuft of microvilli on EC cells –> serotonin released from EC cells into lamina propria –> bind 5-HT3 receptors on extrinsic sensory neurons in (1) vagal/parasympathetic nodose ganglia or (2) splanchnic/sympathetic in dorsal root ganglia
Why don’t we just have neurons from the brain contacting epithelial cells of the gut?
Epithelial cells of the gut turn over every few days, so need EC cells in epithelial lining to release serotonin into lamina propria (paracrine action), where 5-HT receptors of neurons are
How does serotonin initiate peristaltic and secretory reflexes?
Serotonin activates intrinsic primary afferent neurons (IPANs)
Mechanical (pressure) or chemical signals in intestinal lumen –> apical tuft of microvilli on EC cells –> serotonin released from EC cells into lamina propria–> bind 5-HT1P receptors on intrinsic primary afferent neurons (IPANs), a type of interneuron –> IPANs secrete ACh (and CGRP)
ACh binds 5-HT4 receptors on presynaptic terminal of its IPAN to amplify release of ACh more
ACh on myenteric neurons synapse onto smooth muscle (peristalsis) and secretory epithelium (secretion)
What are two ways serotonin acts as a paracrine messenger and neurotransmitter in the gut?
1) Intrinsic primary afferent neurons (IPANs) to initiate peristaltic and secretory reflexes
2) Extrinsic primary afferent neurons to transmit information to CNS
What ultimately causes nausea and vomiting?
Excessive serotonin
How does blocking 5-HT3 receptors prevent nausea and vomiting?
Block vagal afferent stimulation (gut can’t communicate with CNS)
Also, can block the chemotrigger zone (CTZ), which is connected to the CNS vomiting center in the NTS
Ex: ondansetron (don’t throw up so you can keep ONDANcing), granisetron
What happens when you have too much 5-HT (taking SSRIs or TCAs)?
GI side effects because SERT in periphery also inhibited –> nausea, diarrhea
After time, receptor desensitization and tolerance so no more GI symptoms
5-HT uptaken by less potent transporters (OCT, DAT)
How are platelets related to serotonin?
Platelets have SERT and uptake lots of serotonin!
Platelets release serotonin and the serotonin enhances platelet aggregation (released in response to damage to blood vessels)
Do we have a lot of serotonin in our plasma?
NO!
What is not stored in EC cells/interneurons or platelets is metabolized in liver and lungs, so very little in plasma
Serotonin and GI tract big picture
Food enters stomach, serotonin released from EC cells to increase peristalsis, cause secretions, and tell CNS that there’s food in the stomach
What to think about for 5HT3, 5HT4, and 5HT1P receptors
5HT3: vomit
5HT4: amplify (but not initiate) signaling for peristalsis/secretion
5HT1P: direct stimulation of peristalsis/secretion
