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PDA Block 2 > Histamine > Flashcards

Histamine Flashcards

1
Q

Histamine

A

-Mediator of immediate allergic and
inflammatory reactions
-
-neurotransmitter and neuomodulator

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2
Q

synthesis/metabolism of histamine

A
  • histidine decarboxylase (an inducible enzyme) creates histamine from histidine
  • alterations in histamine degrading enzymes can account for histamine intolerance (1% of population)
  • genetic or acquired
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3
Q

Where is most histamine found

A

-lungs, skin, GI tract

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4
Q

Describe histamine in mast cells

A
  • it is synthesized and stored in secretory granules
  • there is a slow turnover bc it is stored here

Yes storage granules!!

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5
Q

Describe histamine is in non-mast cells (gastric mucosa cells, epidermins, neurons)

A

when histamine is in non-mast cells there are no granules. it is continuously synthesized and released so there is a rapid turnover

no storage granules!

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6
Q

effects of histamine release

A
  • within seconds:
  • burning, itching,
  • **intense warmth
  • **skin reddens
  • **BP decreases: increase vascular permeability
  • HR increases

within minutes;

  • BP recovers
  • hives appear
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7
Q

mechanism of release of mast cell histamine

A
  • Antigen-antibody reaction (IgE)
  • requires prior exposure to an antigen
  • Ca dependent
  • also other mediators are released as well not just histamine but histamine is the main one
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8
Q

Is the only way to get histamine released from a mast cell via an Antibody-Antigen response

A

NO!!!

histamine can be released via direct stimulation/ without prior exposure

-but this is of clinical concern bc it causes and inflammatory response and it is kind of scary that drugs and toxins can directly cause this on first exposure

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9
Q

What is the mechanism of release of direct stimulation causing histmaine release from mast cells

A

an increase in intracellular Calcium

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10
Q

What are some other stimuli that release histamine

A
  1. cold urticaria- cold hives
  2. Cholinergic urticaria
  3. Solar urticari a
  4. non-specific cell damamge
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11
Q

Cholinergic urticaria

A

-increased sympathetic nevous activity (seen with exercise and stress) stimulate cholinergic fibers innervating sweat glands to release acetylcholine, leading to mast cell degranulation

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12
Q

Cromolyn

A
  • anti-inflammatory agent that stabilizes mast cell membrane to prevent the release of histamine
  • it prevents mast cell degranulation
  • therapeutic use: prohylaxis of bronchospasm (allergen or exercise-induced)
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13
Q

Omalizumab

A

-decreases the amount of antigen specific IgE that normally binds to and sensitizes mast cells
-an IgG antibody for which the antigen is the Fc region of the IgE antibody (basically Omalizumab is antibody that binds to the IgE antibody)
-adverse effects: anaphylaxis
therapeutic use: patients with severe asthma that is poorly controlled or patients with severe concomitant allergic rhinitis

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14
Q

Does Omalizumab only work on IgE that is bound to mast cells

A

NO! it activate high affinity receptors (FcERI) on mast cells and low affinity receptors (FcERII, CD23) on toher inflammatory cells

-so although we use it to stope IgE on mast cells so that less histamine is release Omalizumab can also inpact other inflammatory/immune cells

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15
Q

What are the four subtypes of receptors for Histamine

A

H1
H2
H3
H4

but there are only drugs for H1 and H2 that we are going to talk about

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16
Q

What is the main effect of histamine on the CV system

A

Vasodialtion
-H1 (endothelial cells)
H2 (vascular smooth muscle cells)

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17
Q

Where is H1 found

A

Endothelial cells

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18
Q

Where is H2 found

A

Vascular smooth muscle

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19
Q

Properties of H1 receptor

A

Gq which increases Ca and also then NO

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20
Q

Properties of H2

A

Gs which increases cAMP

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21
Q

H1 effector system is coupled to

A

increase Ca (endothelial cells which then increases NO and leads to vasodilation)

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22
Q

H2 effector system is coupled to

A

increase cAMP

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23
Q

How do the H1 receptors lead to vasodilation

A

H1 receptors located on endothelial cells results in increase in calcium and activation
of nitric oxide synthase

NO is a vasodilator in VSM

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24
Q

How do H2 receptors lead to vasodilation

A

H2 receptors located on vascular smooth muscle cells results in increase in cAMP

  • decreasing intracellular calcium
  • decreasing the rate of myosin phosphorylation.
  • Inhibit constriction = vasodilation
25
Q

hypothetical question: If there were H1 receptors on vascular smooth muscle what would happen

A

constriction bc H1 causes an increase in Ca. so good thing it is in the endothelial cells and can cause the increase in NO and therefore vasodilation

26
Q

How does histamine impact blood pressure

A

-in general, histamine dilated resistance vessels and causes an overall fall in BP

27
Q

How does histamine impact BP

A

it causes an increase in vascular permeability by acting on H1 receptors

-located on post-capillary venules-endothelial cells, when histamine binds to the H1 receptor is increases Ca which causes the endothelial cells to contract and expose the basement membrane.
this makes the m=basement membrane freely permeable to plasma proteins and fluid.

increase the vascular permeability which decreases BP

28
Q

What does histamine do to the bronchioles

A

stimulates the H1 receptor which increases Ca and leads to contraction

29
Q

What does histamine do to the exocrine glands

A
  • GI secretory tissue (parietal cell)
  • H2 receptor leads to gastric acid secretion
  • this is where H2 antagonists work
30
Q

What does histamine do to the peripheral nerve endings

A

it binds to the H1 receptor and causes pain and itching

31
Q

Describe the neuroendocrine (Central) Effects of histamine

A

-it binds to the H1 receptor and causes increased arousal/ wakefulness

32
Q

List the first generation H1 receptor blockers

A

-Diphenhydramine

-Dimenhydrinate:Contains both diphenhydramine and
chlorotheophylline

  •  Chlorpheniramine
  • Promethazine: Also dopamine blocker
33
Q

List the Second generation H1 receptor blockers

A
  • Fexofenadine
  • Loratadine
  • Cetirizine
  • Desloratidine
34
Q

Describe the pharmacology of the H1 blockers

A
  • specifically reversible antagonists of the H1 receptors located in both the periphery and the brain (therefore can lead to CNS effects like drowsiness)-considered and inverse agonist bc reduce constitutive activity at the receptor and compete with histamine
  • First generation drugs have other non-specific effects unrelated to the H1 receptor blockade
  • second generation have little to no CNS effects
35
Q

histamine released during an allergic reaction casues

A

blood vessels to dilate and causes redness, swelling itching, and changes in the secretions of nasal tissue (ie vascular permeability)

36
Q

Major pharmacological effect of H1 antagonists

A

-reduce the symptoms associated with allergic responses/inflammation

  • inhibition of vascular permeability
  • suppress itching
37
Q

CNS side effects of H1 antagonists

A
  • specifically mostly the first generations

- most common is slowed reaction times, decreased alertness

38
Q

Pharmacokinetics of H1 antagonist

A
  • oral administration
  • rapid absorption: peak concentration 1-2 hours

-widely distributed: however 2nd generation (fexofenadine, loratadine, desloratadine, cetirizine) less likely to enter the brain

39
Q

Metabolism of the H1 antagonists

A

-Extensive liver metabolism
-2nd generation:
some are metabolized by P450 enzymes

40
Q

terfenadine is metabolized to

A

fexofenadine

41
Q

Loratadine si metabolized to

A

desloratadine

42
Q

Cetirizine

A

is active metabolite of hydroxyzine

43
Q

Sedation is most common with which generation of H1 anatagnists

A

1st generation

  • due to inhibition of central H1 effect
  • central anticholinergic effect
44
Q

What are the reasons for why first generation antihistmines have a sedative effect

A
  1. enters CNS
  2. blocks h1 receptors that mediate arousal (in CNS)
  3. Are nonspecific and also have structures that allow them to block cholinergic receptors in CNS
45
Q

other anti-muscarinic (anticholinergic) side effects

A

seen only with some first generation drugs

-dry mouth, dryness of respiratory passages, urinary retention

46
Q

which second generation drugs are no longer marketed in the US

A

Terfenadine and Astemizole

prolong QT interval

47
Q

When are H1 antagonists less effective for allergies

A
  • –   Allergens abundant –  -Exposure prolonged – 

- Nasal congestion prominent

48
Q

What is the most potent first generation drug

A

chlorpheniramine also causes less sedation in some patients

49
Q

What is the first generation drug with the most sedativeeffects

A

Diphenhydramine

50
Q

What is the second generation drug with the most sedative effects

A

-cetirizine

51
Q

Tell me about motion sickness

A

-it involves muscarinic cholinergic transmission

52
Q

Which drugs have an anti-cholinergic effect

A
  • dimenhydrinate (dramamine)
  • promethazine (phenergan)
  • diphenhydramine ( benadryl)
53
Q

What do H2 receptor antagonists cause

A

relief of symptoms peptic ulcer disease

and gastroesophageal reflux disease (GERD)

54
Q

how do the H2 histamine receptors lead to increase in stomach acidity

A

stimulation of H2 receptors on parietal cells increases adenyl cyclase which increases cAMP which activate PKA which increases acid!!!

55
Q

Pharmacological profile for H2 antagonist

A
  • reversible competitive inhibitors specific for the H2 receptor on the basolateral membrane of parietal cells
  • inhibit nocturnal gastric acid secretion which is a big determinant in healing of ulcers
  • also reduced volume of gastric acid and H+ concentration
56
Q

Pharmacokinetics of H2 anatagonists

A

oral administration rapid

57
Q

adverse effects for H2 antagonists

A

incidence is really low!! except for cimetidine (bc cimetidine is metabolized by P450s)

-any drug that inhibits gastric acid secretion or pH can alter bioavailability of other drugs bc it can change their absorption

58
Q

Side effects of cimetidine

A

inhibits P450 metabolism and therefore prolongs the half life of other drugs

59
Q

MAJOR USE OF H2 ANATGONISTS

A

Uncomplicated GERD

PDA Block 2 (13 decks)

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