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BIOL2049 S1 > Histamine and 5-HT > Flashcards

Histamine and 5-HT Flashcards

1
Q

Histamine and 5-HT are both what?

What is this?

A

biogenic amines

A biogenic (produced or brought about by living organisms) substance with one or more amine group

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2
Q

What size is histamine and 5-HT?

How do they act?

A

They are small molecules

Molecular weight of roughly 100

They act as local hormones or autacoids

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3
Q

What is histamine and 5-HT important for?

A

As neurotransmitters, local hormones in vasculature and in smooth muscle

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4
Q

Tell me about how histamine is linked to human diseases

and what histamine is involved with each?

A

Allergy (H1): A sensitivity to a specific substance (allergen), that is contacted through the skin, inhaled into the lungs or injected

Peptic ulcer (gastric ulcer) (H2): A break in the lining of the stomach, first part of the small intestine, or occassionally the lower oesophagus

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5
Q

Tell me the structure of Histamine, label the groups at each terminus?

What is the pKa of the terminal groups and how is this affected in physiological conditions?

A
  • pKa is defined as the pH where a drug exists as 50% ionized and 50% unionized
  • on C terminus the ring like structure is called an Imidazole ring
  • Under physiological conditions there is a pH of about 7, so in this case the ring would be neutral, but the N terminus would be NH3+
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6
Q

What is the source of histamine?

A

Histadine

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7
Q

Tell me about the synthesis of histamine?

A

Histidine has an extra COOH group on N terminus, so simply need to remove COOH to form histamine

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8
Q

Tell me about the dietary sources of histamine?

A
  • Histidine decarboxylase found in several bacteria
  • Histamine found in red wine, yeast extracts, smoked fish and meat
  • Dietary histamine does not contribute to the body’s pool of histamine (as is destroyed by bodies acid)
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9
Q

Metabolism of histamine

A
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10
Q

Tell me where histamine can be stored and how much in those locations?

A
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11
Q

In the cytoplasm of mast cells, there are mast cell granuels. What do these contain?

A

Mast cell granules contain histamine bound to a proteoglycan core, usually heparin. Might help protect from degradation so isn’t metabolized

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12
Q

What happens when the mast cell is in a resting state and an activated state?

A
  • Under certain conditions the mast cells can be activated to release the granules to the environment
  • The granules also contain proteolytic enzymes such as tryptase and chymase.
  • Activation of the mast cells causes the granules to fuse with the cell membrane and release their contents (histamine also released and all contributed to biological consequences)
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13
Q

State 3 factors which causes release of histamine from the mast cell due to activation of the cell?

A
  1. IgE dependent release
  2. Other stimuli
  3. Non-specific release
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14
Q

Tell me about IgE dependent release of histamine?

A
  • Mast cells have receptors for IgE on their cell surface.
  • These bind IgE and when the cell is re-exposed to allergen IgE is crosslinked and the mast cell granules are released.
  • The IgE dependent release of histamine is associated with the symptoms of allergic disease
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15
Q

Tell me how other stimuli cause release of histamine from the mast cells?

A
  • Mast cells can be activated by bacterial products such as lipopolysaccharide (LPS).
  • They are also activated by complement peptides such as C3a and C5a

​

  • Both these mechanisms involve specific receptors on the mast cell surface.
  • Histamine release occurs during bacterial infections and initiates an inflammatory response which recruits other elements of the immune system to destroy the bacteria
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16
Q

Tell me about non-specific release of histamine from the mast cells

A
  • A number of basic drugs such as morphine and tubocurarine (NMJ drug) release histamine by non-receptor actions.
  • Histamine is also released following trauma to the tissues. This includes UV radiation, burns, and changes in osmolarity
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17
Q

Tell me about the type of histamine receptors and where they are generally located in the body?

A
  • H1 - wide distribution in cardiovascular system, smooth muscle and peripheral nerves
  • H2 - regulates gastric acid secretion in the stomach, increases rate and output of the heart
  • H3 - found in the CNS
  • H4 - found on inflammatory cells
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18
Q

The comparison between the different histamine receptors in the body

A
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19
Q

The actions of the histamine receptor, H1, are mainly located in the vasculature system. Tell me some of these actions?

What do these actions cause?

A
  • Vasodilation (causes redness and heat)
  • Increased vasculature permeability (causes swelling)
  • Stimulation of peripheral nerves (causes pain/itch)
  • Smooth muscle contraction (causes asthma)
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20
Q

Vasodilation, caused by H1

A
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21
Q

Increased vascular permeability caused by H1

A
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22
Q

Stimulation of peripheral nerves, caused by H1

A
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23
Q

Smooth muscle contraction, caused by H1

A
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24
Q

Tell me some actions of histamine on the cardiovascular system?

Generally and specifically on the heart, arterioles, veins, capillaries and arteries

A
  • Histamine acts on the heart to increase rate and force of contraction
  • Dilation of arterioles causes a fall in peripheral resistance
  • Veins are constricted increasing pressure in the venules
  • Capillaries are dilated
  • Arteries are constricted
  • Small doses of histamine cause a drop in peripheral resistance leading to a drop in blood pressure
  • Large doses of histamine cause a profound decrease in blood pressure and a loss of fluid from the capillaries can cause circulatory collapse (Anaphylactic Shock)
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25
Q

Tell me about the wheal-and-flare reaction of histamine when injected in the skin?

A
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26
Q

Whats the classical H1 antagonist?

How is it given?

What are some sideeffects?

A
  • The classical H1 antagonist is mepyramine
  • It is orally available and has an excellent safety profile.
  • Side effects include drowsiness and effects on cholinergic receptors.
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27
Q

Whats a newer H1 antagonist thats now available? Why was this one developed?

A

Newer H1 antagonists such as cetirizine have been developed and cause fewer problems with drowsiness (more specific to the peripheral H1 receptor)

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28
Q

Tell me some uses of H1 receptor antagonists?

A
  • Treatment of allergies -oral, topical applications
  • Sedative actions
  • Local anaesthetic actions
  • Motion sickness - safe though they can cause drowsiness
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29
Q

Tell me some actions of histamine on the H2 receptor?

A
  • Stimulates gastric acid secretion
  • Regulates cardiac output and rate
  • Modulates actions of immune cells
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30
Q

Tell me the regulations of gastric acid involving the histamine receptor H2?

A
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31
Q

Tell me the actions of H2, in the cardiac system?

A
  • Histamine stimulates isolated （in vitro） heart preparations to increase rate and force of contraction
  • This is due to direct actions on the cardiac muscle but also indirect actions via the release of noradrenaline from the adrenergic nerves
  • The response of the heart in vivo is largely regulated by autonomic reflexes due to change in blood pressure
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32
Q

Tell me some other actions of H2 in the body?

A
  • H2 receptors are found on a number of cells in the immune system including mast cells and lymphocytes.
  • They may provide a negative feedback inhibiting the release of histamine from degranulating mast cells
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33
Q

What is the classical H2 receptor antagonist?

How is it given?

A

The classical H2 receptor antagonist is cimetidine.

It is orally available and has an excellent safety profile

34
Q

Even though Cimetidine has an excellent safety profile, what does it inhibit and what effects does this have?

A

Cimetidine inhibits cytochrome P450 and can retard the metabolism of a range of different drugs such as anticoagulants and tricyclic antidepressants.

35
Q

Tell me some uses of the H2 receptor antagonist?

A
  • Widely used to treat the symptoms of gastric ulcers
  • Also used in reflux oesophagitis
  • Some H2 antagonists have anti-cancer activity
36
Q

Tell me some actions of H3?

A
  • Histamine is found in the brain and functions as a neurotransmitter.
  • Histaminergic neurons originate in the hypothalamus and extend to virtually all parts of the brain.
  • Histamine release in the CNS follows a distinct circadian pattern with release occurring during the day but not at night.
37
Q

Tell me about H3 receptor antagonists?

A

There are no H3 antagonists in clinical use

38
Q

What is Thioperamide used for?

A

research into the functions of the H3 receptor

39
Q

What are the poterntial uses of the H3 receptor antagonists?

A
  • control sleep/wake cycles and sedation
  • control of food and water intake
  • thermoregulation
40
Q

Where have H4 receptors been identified on?

A

inflammatory cells

41
Q

What do H4 receptors appear to regulate?

Tell me about the H4 agonists/ antagonists?

A

They appear to regulate the cytokine networks in the inflammatory response

The agonists/ antagonists of H4 receptors are not fully elucidated

42
Q

Tell me about the role of histamine in tumours and foetus?

A
  • Mast cells are often found associated with tumours. It is not clear if they are facilitating tumour development (eg heparin from mast cell granules increasing angiogenesis) or part of the host defence against the tumour.
  • The growing fetus also contains and produces substantial amounts of histamine, and the placenta produces large amounts of diamine oxidase (histaminase). Histamine has been assumed to contribute to embryo-uterine interactions due to its vasoactive, differentiation and growth-promoting properties.
  • These may involve alternative histamine receptors
43
Q

Histamine plays an important role in intiatng the body’s immune response to the presence of foreign antigens and pathogens. A primary source of histamine released during inflammatory conditions are:

A. B cells

B. Enterochromaffin-like cells

C. Presynaptic nerve terminals

D. Mast cells

E. T lymphocytes

A

D. Mast cells

44
Q

Site of action for H2 receptor antagonists with respect to acid production inhibition:

A. Parietal cells

B. Chromaffin cells

C. Mast cells

A

A. Parietal cells

45
Q

Which class of antibody is associated with an allergic reaction?

A. IgA

B. IgE

C. IgM

D. IgG

A

B. IgE

46
Q

Which of the following enzyme is essential for the conversion of histidine to histamine?

A. Histidine amylase

B. Histidine hydrolase

C. Histidine decarboxylase

D. Histidine phosphorylase

A

C. Histidine decarboxylase

47
Q

Which of the following statements about histamine is correct?

A. Histamine is stored in peripheral nerve endings

B. Histamine is released from mast cells following an allergic challenge

C. Histamine is a vasoconstrictor

D. Histamine is an essential amino acid

A

B. Histamine is released from mast cells following an allergic challenge

48
Q

Which of the following activites occurs following stimulation of H2 receptors?

A. Vasodilation

B. Uterine contraction

C. Bronchial smooth muscle contraction

D. Enhanced secretion of hydrochloric acid in the stomach

A

D. Enhanced secretion of hydrochloric acid in the stomach

49
Q

Which of the following statements about histamine is not correct?

A. It is a bronchodilator

B. Large scale release of it may cause a fall in blood pressure

C. Large scale release of it may cause a fall in blood volume

D. Histamine release contributes to the symptoms of anaphylaxis

A

A. It is a bronchodilator

50
Q

Histamine exerts the following actions except?

A. Dilation of large blood vessels

B. Dilation of small blood vessels

C. Stimulation of isolated guinea pig heart

D. Itching

E. Increasing vascular permeability

A

A. Dilation of large blood vessels

51
Q

What is the full name for 5-HT and what is it also known as?

A

5-Hydroxytryptamine (5-HT) is also known as serotonin

52
Q

Where is 5-HT found?

A

The CNS, GI tract and in platelets

53
Q

What is 5-HT important for?

A

An important neurotransmitter and plays a key role in the GI tract and vascular system

54
Q

How is 5-HT linked to human disease?

A
  • Depression by 2030, the largest contributor to disease burden (WHO, 2008)
  • Migraines some food may change levels of 5-HT in body and therefore casue the onset of migraines
55
Q

Levels of 5-HT and symptoms

A
56
Q

Whats the structure of 5-HT?

Label the groups present

A
57
Q

Synthesis of 5-HT

A
58
Q

What are the dietary sources of 5-HT?

A
  • 5-HT is found in bananas, strawberries, pineapples and tomatoes
  • Dietary intake of 5-HT does not affect the body’s pools of 5-HT but is rapidly metabolized and excreted in the urine
59
Q

Metabolism of 5-HT

A
  • High level of 5-HT, test HIAA in urine samples could signify this as they are associated to one another.
  • People who suffer with migraines have urine tested and tend to have high levels of HIAA which then links to high levels of 5-HT
60
Q

Tell me about the storage of 5-HT in the following: CNS, Gut, platelets

A
  • 5-HT is synthesized in the CNS and in the enterochromaffin cells in the gut
  • Though 5-HT is an important neurotransmitter 90% of the body’s 5-HT is stored in the gut
  • 5-HT is taken up by platelets as they pass through the intestinal circulation and stored in their granules, but they do not synthesize it
  • The average adult contains only 10mg of 5-HT
61
Q

What drugs alter 5-HT levels and how?

A
  • Fenfluramine, an appetite suppressant, depletes 5-HT levels in the CNS. Used to be used to treat people with obesity. But has lots of side effects which is why no longer used
  • Ecstasy (3,4-methylenedioxy methamphetamine) causes the release of 5-HT in the CNS followed by a drop in tissue levels of 5-HT
  • A carbohydrate rich diet can boost levels of 5-HT promoting feelings of well-being and sleepiness
62
Q

How many 5-HT receptors are there and tell me them?

A
  • 5-HT has many functions and can interact with 7 receptor families, some of which are subdivided
  • There are important species differences, and several receptor sub-types were originally described in one setting and have been re-classified as the pharmacology became clearer
63
Q

Tell me the 5-HT receptors, the subtype, the transducer and structure

A
64
Q

5-HT1 receptors summary

A
65
Q

5-HT2-3 receptors summary

A
66
Q

5-HT4-7 receptor summary

A
67
Q

Where do 5-HT1 receptors mainly occur?

What activates these receptors?

What are these receptors important for?

A
  • These occur mainly in the CNS (5-HT1D receptors are also on cerebral blood vessels).
  • Activation of these receptors results in neural inhibition and vasoconstriction
  • 5HT1 receptors are important in mood and behavior, thermoregulation, feeding and sleep. Linked to migraines
68
Q

The following is about 5-HT1 agonists and antagonists…

  • What is the most effective drug as a 5-HT1D agonist
  • The classical one?
A
  • The most effective drug is sumatriptan, a 5-HT1D agonist
  • Several antagonists of different 5-HT receptor sub-types are used to elucidate 5-HT pharmacology, but none are currently in clinical use
  • The classic 5-HT1 antagonist is methiothepin which acts on all the 5-HT1 receptor subtypes
69
Q

Where do 5-HT2 receptors mainly occur?

Where are they widely distributed?

A

5-HT2 receptors occur in the CNS and are also widely distributed in the periphery

70
Q

What is an agonist at central 5-HT2 receptors that cause hallucinations?

A

Lysergic acid diethylamine (LSD)

However, LSD is an antagonist of 5-HT2 receptors in the periphery

71
Q

Tell me the actions of LSD on 5-HT2 receptors?

A
  • LSD acts as a 5-HT2 receptor agonist in the CNS
  • It inhibits the firing of the 5-HT containing neurons of the raphe nuclei
  • LSD alters perception so that sights and sounds appear distorted and fantastic
  • LSD has been reported to precipitate attacks in schizophrenia patients
  • LSD: Lysergic acid diethylamide
72
Q

Tell me some of the 5-HT2 antagonists and their uses?

A
  • 5-HT2 receptor antagonists include methysergide and ketotifen
  • Many 5-HT2 antagonists will also affect other 5-HT receptors as well as a-adrenoceptors and histamine receptors which limits their use in vivo
  • Methysergide was used to treat migraine before the development of the ‘triptans’
73
Q

Where are 5-HT3 receptors found and what do they cause when in these locations?

A
  • 5-HT3 receptors are found mainly in the peripheral nervous system where they evoke pain
  • 5-HT3 receptors are also found in the brain where they are involved in the vomiting reflex
74
Q

Tell me the uses of 5-HT3 antagonists

A
  • 5-HT3 antagonists such as ondansetron are used as anti-emetics.
  • They are effective at controlling the severe vomiting and nausea that occurs with cancer chemotherapy.
  • These drugs may also be anxiolytic
75
Q

Where are 5-HT4 receptors mainly found?

What is their main physiological role?

Name an agonist and its role?

A
  • 5-HT4 receptors are found in the CNS but their main physiological role appears to be in regulating GI motility.
  • 5-HT4 receptor agonists such as tegaserod are used to relieve the abdominal discomfort, bloating, and constipation associated with irritable bowel syndrome. Its use was also approved to treat chronic idiopathic constipation.
76
Q

Tell me 5-HT role in migraines?

A
  • 5-HT is known to cause vasoconstriction in the cerebral arteries
  • 5-HIAA is found in the urine of patients with migraine
  • Drug companies spent a lot of time and money looking for a 5-HT1 antagonist to treat migraine
77
Q

Tell me about 5-HT role in the gut?

Tell me about peristalsis and 5-HT?

A
  • 5-HT stimulates GI motility both directly via 5-HT2 receptors on the smooth muscle cells and indirectly via 5-HT3 and 5-HT4 receptors on enteric neurons
  • 5-HT also stimulates fluid secretion and elicits nausea and vomiting by stimulating 5-HT receptors in the stomach
  • Peristalsis is mediated in part by the actions of 5-HT released from chromaffin cells by distention of the gut or vagal stimulation
78
Q

Tell me aboout 5-HT in the cardiovascular system?

What do the actions depend on?

It can act directly and indirectly. Tell me about the indirect effects?

What does injection of 5-HT lead to?

A
  • The actions of 5-HT in the cardiovascular system depend on the size of the vessel, species, and sympathetic activity
  • 5-HT has direct effects but can also act indirectly via release of Nitrogen oxide (NO) from the endothelial cells and inhibiting noradrenaline release from the sympathetic nerve terminals
  • Injection of 5-HT leads to an initial rise in blood pressure as the large vessels constrict followed by a fall as the arterioles dilate
79
Q

Tell me about 5-HT effects in circulation?

A
80
Q

Tell me about 5-HT in platelets…

What it acts on?

What does it cause when binds to the above receptor?

A
81
Q

Serotonin: platelet effects–

A. promotes aggregation

B. inhbibits aggregation

C. No effects

A

A. Promotes aggregation

82
Q

Greater than 90% of serotonin is located here…

A. platelets

B. Raphe nucleus (brain stem)

C. enterochromaffin cells of the GI tract

D. lungs

E. cerebral cortex

A

C. enterochromaffin cells of the GI tract

BIOL2049 S1 (9 decks)

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