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Immunity Week 2 > ICL 8.1: Immunopharmacology > Flashcards

ICL 8.1: Immunopharmacology Flashcards

1
Q

how do you make histamine?

A

histidine (AA) –> histamine via L-histidine decarboxylase

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2
Q

where is histamine synthesized?

A

mast cells and basophils

super high concentrations but slow turnover

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3
Q

which tissues are rich in mast cells?

A
  • lungs
  • skin
  • GI mucosa
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4
Q

where is histamine stored?

A

in granules of mast cells complexed with heparin

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5
Q

what does ECL stand for?

A

enterochromaffin-like cells

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6
Q

what are ECL cells?

A

neuroendocrine cells in gastric mucosa

secretion is stimulated by gastrin

ECL cells are found in the stomach!

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7
Q

what is the pathway through which mast cells are activated?

A
  1. antigen cross links IgE antibodies bound to FcεR on mast cells
  2. tyrosine kinase cascade initiates
  3. Ca+2 enters the cell
  4. increased Ca+2 levels trigger fusion of vesicles with membrane and you dump out the contents of the vesicles which have histamine and other stuff in them

Ca+2 also activates PLA2 which frees AA and triggers PAF, PGD2, and LTC4 production

Ca+2 also triggers production of TNFα and interleukins

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8
Q

what does an increase of Ca+2 inside a mast cell cause?

A
  1. triggers fusion of vesicles with membrane and you dump out the contents of the vesicles which have histamine and other stuff in them
  2. activates PLA2 which frees AA and triggers PAF, PGD2, and LTC4 production
  3. triggers production of TNFα and interleukins
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9
Q

what is inside the vesicles of mast cells?

A

histamine

heparin

proteases

ECF-A

NCF

TNFα

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10
Q

what things entering the mast cell can cause increased Ca+2?

A

anaphylatoxins C3a and C5a

bradykinin

substance P

venoms

compound 48/80

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11
Q

how can certain drugs cause mast cells to release the contents of their vesicles?

A

certain drugs seen to interact with mast cells in the SKIN, not other locations, and trigger the release of histamine

we have no idea how they do this!

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12
Q

which drugs can trigger mast cells to release histamine?

A
  1. opioids = morphine and codeine
  2. tubocurarine
  3. vancomycin
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13
Q

how can physical damage cause mast cells to release histamine?

A

like a scratch of UV light can lead to physical damage that increases Ca+2 and leads to histamine release

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14
Q

what two things can cause histamine to be released from mast cells?

A
  1. drugs

2. physical damage

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15
Q

what drug inhibits mast cell activation?

A

epinephrine

epinephrine increases the concentration of cAMP which will keep Ca+2 levels down by inhibiting protein kinase

this inhibits activation of mast cells!

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16
Q

what’s the function of ECL cells?

A

they’re sorta like mast cells and they are found in the stomach!

they are activated by gastrin and acetylcholine which increase Ca+2 and cause ECL cells to release histamine

histamine stimulates acid secretion!

most of the histamine in the stomach comes from ECL, not much from mast cells

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17
Q

where is histamine inactivated?

A

histamine is an autacoid or locally acting hormone

so it is synthesized, has its action and is normally inactivated in the same tissue

histamine that is released in or entering the blood stream is inactivated in the LIVER

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18
Q

what are the different histamine receptors?

A

H1-H4

expression of these receptors is tissue and species dependent

H1 and H2 are the only ones that we have drugs to target

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19
Q

where are H1 receptors found?

A

smooth muscle cells in:

  • bronchioles
  • GI tract
  • uterus
  • endothelial cells

H1 receptors cause smooth muscles to contract by elevating Ca –> activates MLCK –> phosphorylates MLC to MLC-P and causes a contraction

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20
Q

what do H1 receptors do when histamine binds to them?

A

H1 receptors cause smooth muscles to contract

they elevate Ca –> activates MLCK –> phosphorylates MLC to MLC-P and causes a contraction

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21
Q

where are H2 receptors bound?

A

smooth muscle of arterioles and precapillary sphincters

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22
Q

which histamine receptors are involved in relaxation of smooth muscles?

A

H1 and H2

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23
Q

which histamine receptors are involved in contraction of endothelial cells?

A

H1 only

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24
Q

what two biological effects can histamine have on the body?

A
  1. smooth muscle relaxation = bigger blood vessels

2. contraction of endothelial cells = edema

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25
Q

what are the effects of histamine on the cardiovascular system?

A
  1. vasodilation
    - relaxation of arteriolar smooth muscle leads to dilation
    - mediated by both H1 and H2 receptors
    - if effect is systemic, there will be a drop in BP
  2. increase in vascular capillary permeability
    - contraction of muscle filaments in endothelial cells of venules leads to cell shape change
    - mediated by H1 receptors
    - proteins and plasma enter tissue leading to edema
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26
Q

what is the pathway through which histamine induces increased vascular permeability?

A
  1. histamine binds to H1 in the endothelial cell
  2. PLC increases Ca+2 levels in the cell
  3. increased Ca increases vascular permeability

PLA2 is also activated which releases AA and leads to PGI2 production which relaxes smooth muscle by increasing cAMP

NO is also activated which elevates cGMP and leads to smooth muscle relaxation

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27
Q

how do you know if histamine will bind to H1 or H2?

A

H1 receptors bind histamine more tightly than H2

so if there’s low histamine levels, mostly H1 will mediate the results

you need higher doses of the histamine to activate H2

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28
Q

what is the pathway through which histamine induces smooth muscle relaxation?

A

histamine binds to H1 or H2

  1. histamine binds to H2 on smooth muscle which activates AC and increases levels of cAMP
  2. cAMP activates PKs which decrease Ca+2 levels in the cell
  3. decreased Ca+2 decreases MLCK activity
  4. MLCPase turns MLC-P into MLC which leads to smooth muscle relaxation
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29
Q

what changes in vitals will you see if there is histamine?

A
  1. decreased BP
  2. increased HR

vasodilation from when histamine binds to H1 or H2 decreases your BP and in response, your heart rate increases to try and adjust for this change

30
Q

what is the “triple response”?

A
  1. inject histamine into someone

the little red spot you see is due to vasodilation where the histamine is injected

  1. if you wait a couple minutes the red spot will expand into a wider area and this is due to activation of nerves which can cause itching and pain
  2. then if you wait a little more, you see a bump form = edema from increased vascular permeability
31
Q

what would you use to alleviate symptoms of allergies?

A

H1 blocker

H1 is involved with both vasodilation and increased capillary permeability and activation of nerve endings

these are some of the things that lead to common symptoms of allergies like edema and itch/pain

so if you block H1 you will elevate allergy symptoms

32
Q

how does histamine effect nerve endings?

A

activates nerve endings

this causes itching and pain!

33
Q

how does histamine effect the smooth muscle in airways?

A

the response varies from species to species

ex. guinea pigs have a lot more H1 receptors so they’ll experience contraction of bronchial muscles
ex. sheep on the other hand have alot of H2 receptors and they’ll experience relaxation of bronchial muscle

34
Q

how do healthy individuals respond to histamine?

A

very little response to histamine

they might have some bronchocontriction but that’s it

on the other hand, a person with asthma would be much more sensitive to histamine and experience more bronchorestriction

this is actually how you diagnose asthma!

35
Q

how does histamine effect gastric secretion?

A

histamine is secreted from ECL cells and binds to H2 receptors and stimulates secretion of gastric acid

  • increased acidity
  • increased intrinsic factor of castle
  • increased volume
36
Q

what does intrinsic factor of castle do?

A

promotes absorption of B12 in the intestines

37
Q

what is used to treat heartburn?

A

H2 blockers!

when histamine binds to H2 in the GI, it causes secretion of gastric acid and increases acidity

so if you block H2 you can treat heartburn, GERD, gastritis and ulcers!

38
Q

how does histamine effect the adrenal medulla?

A

histamine binds to H1

causes release of catecholamines like epinephrine and norepinephrine

epi/nor epi are vasoconstrictors and lead to a secondary rise in BP in patients with pheochromocytoma

pheochromocytoma = tumor of adrenal gland that causes adrenal gland to over-secrete epinephrine

39
Q

how does histamine effect the CNS?

A

histamine is a neurotransmitter in the brain

it does NOT readily penetrate blood/brain barrier

when it’s injected into the cerebral ventricles it has a wide variety of effects and can bind to H1, H2 or H3

ex. histamine binding to H1 in the CNS = wakefulness

so blocking H1 receptors in the CNS makes people sleepy!

40
Q

what are the 3 clinical uses of histamine?

A
  1. test for bronchial hyperreactivity aka asthma
  2. used to asses gastric secretory ability
  3. used to test for pheochromocytoma

however, none of these are actually practiced aka histamine is useless

41
Q

what is the difference between old and new allergy drugs?

A

H1 receptor antagonists are used to treat symptoms of allergies

newer drugs are more selective for H1 receptors and have less side effects

there’s also less sedation associated with the newer drugs so people don’t get sleepy on allergy mediacations

42
Q

what is the structure of older H1 blockers used to treat allergies?

A

they have a positive charge but also lipophilic aromatic rings

since they’re lipophilic they get absorbed easily and get across the blood-brain barrier

this is why the older drugs cause sedation!!

ex. diphenhydramine = Benadryl

43
Q

what is an example of an older H1 blocker drug used to treat allergies?

A

diphenhydramine = benadryl

44
Q

what is terfenadine?

A

it’s a “newer” H1 blocker

it’s a little more water soluble so it can’t cross the blood-brain barrier = no sedation

terfenadine is metabolized by CYP3A4 into fexofenadine = allegra

45
Q

what’s the problem with terfenadine?

A

terfenadine is metabolized by CYP3A4 into fexofenadine = allegra

the problem was that CYP3A4 is blocked by stuff like ketoconazole, erythromycin and grapefruit juice

if you block the metabolism of terfenadine it’ll accumulate in your body which blocks the potassium channels in your heart which prolongs the QT interval and could kill you from arrhythmias!!!

46
Q

which drugs are “newer” H1 blockers?

A
  1. terfenadine = Seldane
  2. fexofenadine = Allegra
  3. loratadine = Claritin
  4. desloratadine = Clarinex
  5. levocetirizine = Xyzal
  6. cetirizine = Zyrtec
47
Q

what is fexofenadine?

A

aka Allegra

it’s an H1 blocker that doesn’t have any sedative effects

you should take it with water because fruit juice decreases its bioavailability

48
Q

what is P-gp?

A

it’s in the gut and pumps drugs from the cells into the lumen = it protects you from drugs!

if you block P-gp, more of the drugs get absorbed into the body

49
Q

what is the relation between loratadine and desloratadine?

A

loratadine is metabolized into desloratadine by CYP3A4 and CYP2D6

50
Q

what’s the mechanism behind how H1 receptors treat allergic reactions?

A
  1. capillary Permeability is strongly antagonized
  2. flare and Itch are strongly antagonized
  3. vasodilation is partially antagonized (H1, H2)

they relieve itching, sneezing and runny nose!

51
Q

what is SAR?

A

hay fever

52
Q

what is urticaria?

A

hives

53
Q

which type of smooth muscle isn’t effected by H1 blockers?

A

bronchiolar smooth muscle

54
Q

what conditions are H1 blockers not useful for treating?

A
  1. asthma
  2. anaphylaxis
  3. angioedema
55
Q

what are the side effects of older antihistamines?

A
  1. sedation
  2. antimuscarinic effects
  3. anti nausea and antiemesis
56
Q

how did older antihistamine drugs cause sedation?

A

they are more lipophilic and can cross the blood-brain barrier

even though we don’t want this in allergy medications, it’s been repurposed and used as a sleep-aid like advil PM!!

diphenhydramine is literally in everything that says PM

57
Q

what are antimuscarinic effects?

A

effects produced by blocking muscarinic acetylcholine receptors in tissues innervated by the autonomic nervous system

older H1 blockers have pronounced muscarinic receptor-mediated anticholinergic effects

effects = dry mouth, throat and respiratory passages, urinary retention, tachycardia, blurred vision, constiptation

ex. diphenhydramine and promethazine

58
Q

what is the antimuscarinic effects of older antihistamine drugs on the mouth and respiratory system?

A

normally, ACh increases secretion

antagonist = dry mouth and respiratory passages

59
Q

what is the antimuscarinic effects of older antihistamine drugs on the bladder?

A

normally, ACh leads to urination

antagonist = urinary retention

60
Q

what is the antimuscarinic effects of older antihistamine drugs on the heart?

A

ACh = decreased heart rate bradycardia

antagonist = increased heart rate; tachycardia

61
Q

what is the antimuscarinic effects of older antihistamine drugs on the eyes?

A

normally ACh = accommodation, mitosis

antagonist = blurred vision, mydriasis

62
Q

what is the antimuscarinic effects of older antihistamine drugs on the sweat glands?

A

normally, ACh = increased secretion

antagonist = hot dry skin, increased temperature

63
Q

what is the antimuscarinic effects of older antihistamine drugs on the GI tract?

A

normally, ACh = increased motility and secretion = diarrhea

antagonist = constipation

64
Q

what are the antimuscarinic effects that older H1 blockers have on the body?

A

dry mouth, throat and respiratory passages

urinary retention

tachycardia

blurred vision

constiptation

65
Q

what are the uses of older H1 blockers that cause antimuscarinic effects?

A

treating the common cold!

if you have a runny nose, maybe you WANT something to stop secretion

66
Q

what is scopolamine used for?

A

motion sickness!

one of the “side effects” of an old H1 blocker is anti- nausea because it also functions as an M receptor antagonists

M receptor is a muscarinic acetylcholine receptor and since old H1 blocker meds aren’t very specific for just H1, they can be repurposed as anti-nausea meds

67
Q

which drugs block cytochrome P450-3A4?

A

ketoconazole

erythromycin

grapefruit juice

ritonavir, indinavir

these drugs block conversion of terfenadineand astemizole to active products

these parent drugs block K+ channels in the heart and increase the QT interval = cardiac arrhythmias

this is why terfenadine and astemizole were withdrawn from the market!

68
Q

how is atropine poisoning related to antihistamine drugs?

A

some older H1 blockers have CNS effects that are similar to atropine poisoning

children are really susceptible to them

CNS effects = excitation, hallucinations, ataxia, incoordination, convulsions, coma, cardiorespiratory collapse, death

69
Q

what are the main differences between newer and older H1 blockers?

A
  1. older drugs:
    - CNS penetration which led to sedation
  • antimuscarinic effects
    2. newer drugs are only useful for allergies whereas older drugs have multiple uses
70
Q

which drugs are classified as “older” 1st generation allergy medications?

A
  1. diphenhydramine
  2. chlorpheniramine
  3. promethazine
  4. meclizine (less sedation than others)
  5. hydroxyzine

Immunity Week 2 (12 decks)

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