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Block 3: GI, Endocrine, Reproductive > Histamine and Serotonin Pharmacology (Week 1--Melega) > Flashcards

Histamine and Serotonin Pharmacology (Week 1--Melega) Flashcards

1
Q

Enterochromaffin-like cells (ECL cells)

A

In gastric mucosa (stomach)

Synthesize, store and release histamine

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2
Q

What stimulates ECL cells to secrete histamine?

A

Gastrin binding to CCK2 receptor on ECL cell

ACh binding to muscarinic receptor on ECL cell

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3
Q

What causes parietal cells to secrete acid?

A

1) ACh
2) Gastrin on CCK2 receptors
3) Histamine on H2 receptors (remember, histamine secretion itself is also stimulated by ACh and gastrin)

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4
Q

What mechanism do ACh, gastrin and histamine use to cause H+ secretion from parietal cells?

A

1) ACh –> Ca2+ increase
2) Gastrin –> Ca2+ increase
3) Histamine –> G-coupled protein –> cAMP

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5
Q

What can inhibit H+ secretion by parietal cells?

A

Prostaglandins –> EP3 receptor –> inhibit cAMP

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6
Q

What is an antacid?

A

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

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7
Q

What is an H2 antagonist?

A

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

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8
Q

What is a proton pump inhibitor (PPI)?

A

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

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9
Q

What do prostaglandins do in the GI tract?

A

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

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10
Q

What is the effect of NSAIDs on the GI tract?

A

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

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11
Q

What is the function of mucus?

A

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

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12
Q

What is serotonin and where is it found?

A

5-hydroxytryptamine

In blood (platelets), gut (EC cells) and neurons (cells in raphe nucleus)

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13
Q

What type of receptors are there for serotonin?

A

Almost all are G-protein coupled receptors (5-HT1P, 5-HT4)

5-HT3 is a ligand gated Na+ ion channel

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14
Q

Where does serotonin in our body come from?

A

Synthesis from tryptophan, not from diet (serotonin we eat is polar and charged and gets metabolized in gut wall and liver before entering blood)

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15
Q

How is serotonin synthesized then metabolized?

A

Tryptophan –> (tryptophan hydroxylase) –> 5-hydroxytryptophan –> (aromatic amino acid decarboxylase) –> serotonin

Serotonin –> (MAO and aldehyde dehydrogenase) –> 5-HIAA (into circulation then eliminated in urine)

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16
Q

How is most of serotonin cleared?

A

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)

17
Q

Enterochromaffin (EC) cells

A

Throughout GI tract, are major source of intestinal serotonin

Note: EC cells and 5-HT interneurons contain 95% of body’s 5-HT

18
Q

How does the CNS know what is going on in the gut?

A

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

19
Q

Why don’t we just have neurons from the brain contacting epithelial cells of the gut?

A

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

20
Q

How does serotonin initiate peristaltic and secretory reflexes?

A

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)

21
Q

What are two ways serotonin acts as a paracrine messenger and neurotransmitter in the gut?

A

1) Intrinsic primary afferent neurons (IPANs) to initiate peristaltic and secretory reflexes
2) Extrinsic primary afferent neurons to transmit information to CNS

22
Q

What ultimately causes nausea and vomiting?

A

Excessive serotonin

23
Q

How does blocking 5-HT3 receptors prevent nausea and vomiting?

A

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

24
Q

What happens when you have too much 5-HT (taking SSRIs or TCAs)?

A

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)

25
Q

How are platelets related to serotonin?

A

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)

26
Q

Do we have a lot of serotonin in our plasma?

A

NO!

What is not stored in EC cells/interneurons or platelets is metabolized in liver and lungs, so very little in plasma

27
Q

Serotonin and GI tract big picture

A

Food enters stomach, serotonin released from EC cells to increase peristalsis, cause secretions, and tell CNS that there’s food in the stomach

28
Q

What to think about for 5HT3, 5HT4, and 5HT1P receptors

A

5HT3: vomit

5HT4: amplify (but not initiate) signaling for peristalsis/secretion

5HT1P: direct stimulation of peristalsis/secretion

Block 3: GI, Endocrine, Reproductive (30 decks)

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