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Pharmacology Block 2 > 06 Histamine > Flashcards

06 Histamine Flashcards

1
Q

How is histamine synthesized?

A

Essential AA L-histadine => Histamine

Histidine decarboxylase using pyridoxal 5-phosphate as cofactor

Inhibited by methylhistidine

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2
Q

What co-factor is needed to synthesize histamine?

A

pyridoxal 5-phosphate

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3
Q

What inhibits histamine synthesis?

A

Methylhistidine inhibits histidine decarboxylase

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4
Q

Inhibition or impairment of what enzymes lead to increased histamine?

A

Diamine oxidase or Histamine N-Methyl Transferase (HNMT)

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5
Q

What is histamine and its functions?

A

Mediator of immediate allergic and inflammatory reactions

Role in gastric acid secretion

NT and neuromodulator

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6
Q

Where is histamine localized?

A

It is ubiquitous

Highest: lung, skin, stomach

Pools of histamine:

Synthesized and stored in secretory granules–slow turnover:

    • heparin-sulfate and ATP (mast cells–in tissue)
    • chondroitin-sulfate (basophils–in blood)

Non-mast cell stores (e.g., epidermal cells, gastric mucosa cells, brain neurons, regenerative and tumor cells)

  • Rapid turnover, no granules, continuously released
  • histidine decarboxylase levels correlate with activity
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7
Q

Histamine found in secretary granule in the blood vs tissue

A

Blood: basophil
Tissue: mast cell

Slow turnover

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8
Q

Difference in turnover and synthesis between histamine stored in granules and non-mast cells

A

Granules: synthesized and stored. Slow turn over

Non-mast cells: continuously synthesized and released–rapid turnover

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9
Q

Defects in what contributes to the flushing seen during alcohol intake (certain Asian populations) and some cases of food poisoning?

A

Defects in the metabolism of histamine by the diamine oxidase (DAO) or acetaldehyde dehydrogenase

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10
Q

What happens within seconds of histamine release? minutes?

A

Seconds:

  • -burning, itching
  • -intense warmth
  • -skin reddens
  • -BP dec
  • -HR inc

Mins:

  • -BP recovers
  • -Hives
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11
Q

Antigen-Antibody reaction

A

Release of mast cell histamine (vasoactive amine)

Prior exposure:

    • induction of IgE-mediated allergic sensitivity to drugs and other allergens
    • response of IgE-sensitized cells to subsequent exposure to allergens

Ca2+ dependent
Release of other mediators (Cytokines)

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12
Q

What is the concern with drugs, peptides, and venoms that promote release of histamine?

A

Stimulate release of histamine directly without prior sensitization– unexpected anaphylactoid reactions

Drugs: succinylcholine, morphine, curare, some antibiotics,
radio contrast media, certain carbohydrate plasma expanders

Vancomycin-induced “red-man syndrome”

Peptides: Bradykinin, complement, substance P (tissue injury)

Venoms: wasp venom

Mech: increase intracellular Ca2+ via number of different pathways

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13
Q

What is the mechanism of direct histamine release without prior sensitization?

A

Drug, peptide, or venom increase intracellular Ca2+ via number of different pathways

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14
Q

Red-Man Syndrome

A

Vancomycin (for serious G+ infections)

Following rapid IV infusion

Rash in face, neck, upper torso

Hypotension

Due to mast cell degranulation (not allergic reaction to vancomycin)

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15
Q

What causes Red-Man syndrome?

A

Vancomycin (for serious G+ infections)

After rapid IV infusion, mast cell degranulation causes rash in face, neck, and upper torso and hypotension

Not an allergic reaction

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16
Q

Is Red-Man syndrome due to an allergic reaction?

A

Due to mast cell degranulation following rapid IV infusion of vancomycin (not allergic reaction)

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17
Q

What other stimuli release histamine (non-Ag-Ab or Drug)?

A

cold urticaria, cholinergic urticaria, solar urticaria, nonspecific cell damage

Cholinergic urticaria–inc sympathetic nervous activity (seen with exercise, stress) stimulates cholinergic fibers innervating sweat glands to release ACh, leading to mast cell degranulation

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18
Q

Cromolyn sodium

A

Inhibit Histamine release

Inhaled anti-inflammatory agent

Mech: stabilizes most mast cell membranes and prevents release of histamine

AEs: safe drug/few side effects

Tx:

  • preventive management of asthma (chronic control)–not rescue
  • allergic rhinitis, conjunctivitis
  • food allergies
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19
Q

What drug stabilizes most mast cell membranes and prevents histamine release for bronchospasm prophylaxis (chronic asthma control)?

A

Cromolyn sodium

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20
Q

What does Cromolyn sodium treat?

A

Tx:

  • preventive management of asthma (chronic control)–not rescue
  • allergic rhinitis, conjunctivitis
  • food allergies
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21
Q

Omalizumab

A

Inhibits histamine release

Monoclonal antibody

Mech: dec amount of Ag specific IgE that normally binds to and sensitizes mast cells
– binds tightly to free IgE in circulation so no affinity for FcRI

SubQ admin

AE: life-threatening anaphylaxis and bleeding

Tx: Allergic asthma

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22
Q

What drug is a monoclonal antibody that binds tightly to free IgE in circulation that normally bind to and sensitize mast cells?

A

Omalizumab

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23
Q

What is a major adverse effect with an omalizumab subQ injection?

A

Life threatening anaphylaxis

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24
Q

What are the histamine receptors?

A

All are GPCRs:

- H1, H2, H3, H4

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25
Q

H1: G protein second messenger and distribution

A

Gq (inc Ca2+, inc NO and inc cGMP)

Smooth muscle, endothelial cells, CNS

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26
Q

H2: G protein second messenger and distribution

A

Gs (inc cAMP)

Gastric parietal cells, cardiac muscle, mast cells, CNS

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27
Q

Effect of histamine-receptor activation of the Cardiovascular system?

A

In general, histamine dilates resistance vessels, increases capillary permeability and causes an overall fall in BP.

In some vascular beds, histamine constricts veins, contributing to edema formation (increased permeability)

H1 and H2 activation

28
Q

Histamine activation in endothelial cells

A

H1 activation results in increase in intracellular Ca2+ and activation of NO Synthase

29
Q

Histamine activation in vascular smooth muscles

A

H2 activation coupled to increase in cAMP

    • decreases intracellular Ca2_
    • decreases rate of myosin phosphorylation
30
Q

H1 receptor on vascular smooth muscles

A

Vasoconstriction of large vessels (less important for effects on BP)

H1 receptors located on vascular smooth muscle cells results in increase in intracellular calcium

31
Q

What histamine receptors are activated for blood pressure control?

A

blood pressure (intravenous injection of histamine or released during systemic anaphylaxis)

Both H1 and H2 receptors

In general, histamine dilates resistance vessels and causes an overall fall in BP

32
Q

What histamine receptor is activated to increase vascular permeability and where is it located?

A

H1 receptors located on post-capillary venules

Inc in Ca2+ causes endothelial cells to contract and expose basement membrane

Freely permeable to plasma proteins and fluid

33
Q

What histamine receptor is located on post-capillary venules and its action?

A

H1 receptors located on post-capillary venules

Inc in Ca2+ causes endothelial cells to contract and expose basement membrane

Freely permeable to plasma proteins and fluid

34
Q

What histamine receptors are on the heart and its actions?

A

Predominantly H2

Increases both cardiac contractility and electrical conduction directly

35
Q

H2 receptors on the heart cause?

A

Increase both cardiac contractility and electrical conduction direction

36
Q

What histamine receptors are located on the bronchioles?

A

H1–contraction

H2–relaxation (minor)

37
Q

What histamine receptors are located on intestinal smooth muscle?

A

H1–contraction

38
Q

What histamine receptors are on GI secretory tissue (parietal cell)?

A

H2–gastric acid secretion

39
Q

What histamine receptors are located on peripheral nerve endings?

A

H1–pain and itching

40
Q

What are the effects of histamine as a neurotransmitter?

A

H1–arousal/wakefullness
H1–decrease appetite

H1 and H2–CV, Thermo, Pain

41
Q

What is the difference between First and Second generation antihistamines?

A

Second generation (Nonsedating antihistamine) drugs have little to no anticholinergic side-effects

Do not easily cross BBB to CNS

42
Q

First Generation H1 Receptor Blockers

A

Ethanolamines:

    • Diphenhydramine
    • Dimenhydrinate

Alkylamines:
– Chlorpheniramine

Phenothiazines:
– Promethazine

43
Q

Second Generation H1 Receptor Blockers

A

Non sedating Antihistamines

Piperidines:

    • Fexofenadine
    • Loratadine
    • Desloratadine

Piperazines:
– Cetirizine

44
Q

H1 Receptor Blockers

A

Specific reversible competitive antagonists of the H1 receptors located in both periphery and CNS
– inverse agonist because reduce constitutive activity at receptor and compete with histamine

Pharmacology
1. inhibit capillary permeability

  1. suppress immediate hypersensitivity reactions in anaphylaxis and allergy (itching)
  2. no effect on blood pressure
  3. no effect on bronchoconstriction
  4. CNS effects:
    - - First gen can stimulate (children) and depress (most common) CNS
    - - some prevent motion sickness via CNS anti-cholinergic effect
  5. Peripheral and central anticholinergic effect
    - - Atropine like (inhibit response to ACh)
    - - dry mucus membranes, urinary retention
  6. Local anesthetic effect:
    - - block nerve conduction (Promethazine)

Pharmacokinetics
1. Admin: Oral (rapid absorption), topical, nasal

  1. Distributed widely
    - - 2nd generation less likely to enter brain
  2. Extensive liver metabolism
    - - 2nd generation:
      • CTP3A4/CYP2D6
      • Active metabolites:
        • Fexofenadine
        • Desloratadine
        • Cetirizine

Major Side effects:

  1. Sedation
    - - most common with 1st gen due to inhibition of central H1 (mediates arousal) AND central cholinergic effect
    - - Cetirizine (2nd gen) most sedative
    - - 1st gen paradoxical CNS stimulation (children)
  2. GI (minor)
    - - loss of appetite, n/v
    - - rare: inc appetite and weight gain
  3. Anti-muscarinic 1st gen
    - - dry mouth, dryness of respiratory passages
  4. CV Toxicity
    - - Early 2nd gen (no longer in US): prolongation of QT interval and polymorphic ventricular contractions
    - - due to inc dosage and in combination with drugs that inhibit P450 metab
    - - no toxicity seen with Loratadine

Tx:

  1. Allergies (acute): rhinitis, urticaria, conjunctivitis
    - - less effective for seasonal allergies
  2. Motion sickness–due to anticholinergic effects
  3. Nonprescription sleeping tablets
  4. Other:
    - - Vestibular disturbances
    - - Chemo induced n/v
    - - Early stage Parkinson’s
45
Q

What antihistamine is the most potent in treating acute allergies with symptoms of rhinitis, urticaria, and conjunctivitis as well as less prone to cause drowsiness?

A

Chlorpheniramine

H1 receptor blocker First gen: Alkylamine

46
Q

What antihistamine is used to treat acute allergies with symptoms of rhinitis, urticaria, and conjunctivitis but causes profound sedation?

A

Diphenhydramine

H1 receptor blocker First gen: Ethanolamine

47
Q

What 2nd generation antihistamines are used to treat acute allergies with symptoms of rhinitis, urticaria, and conjunctivitis?

A

Loratadine
Desloratadine
Fexofenadine
Cetirizine (higher incidence of sedation)

48
Q

What antihistamines are used to treat motion sickness?

A

Due to anticholinergic effects

H1 receptor blocker First gen:

Promethazine
Dimenhydrinate
Diphenhydramine

Scopolamine (muscarinic receptor antagonist)

49
Q

What antihistamine is used as a nonprescription sleeping tablet?

A

Diphenhydramine

50
Q

What antihistamine is used to treat vestibular disturbances?

A

Dimenhydrinate

51
Q

What antihistamine is used to treat chemotherapy induced n/v?

A

Promethazine

52
Q

What antihistamine is used to treat early stage Parkinson’s?

A

Diphenhydramine

53
Q

What does chlorpheniramine treat?

A

Acute allergies–most potent and less prone to cause drowsiness

54
Q

What does diphenhydramine treat?

A
  • Acute allergies–profound sedation
  • Motion sickness
  • Nonprescription sleeping tablet
  • Early stage Parkinson’s
55
Q

What does loratadine treat?

A

Acute allergies

56
Q

What does desloratadine treat?

A

Acute allergies

57
Q

What does fexofenadine treat?

A

Acute allergies

58
Q

What does cetirizine treat?

A

Acute allergies–higher incidence of sedation compared to other 2nd gen H1 receptor blockers

59
Q

What does promethazine treat?

A

Motion sickness

Chemotherapy induced n/v

60
Q

What does dimenhydrinate treat?

A

Motion sickness

Vestibular disturbances

61
Q

H2 Receptor Antagonists

A
  1. Relief of symptoms peptic ulcer disease
  2. Gastroesophageal reflux disease
  3. Peptic ulcer secondary to H. pylori infection
  4. gastric injury by NSAIDs

Physio:

  • histamine released from mast cells and enterochromaffin-like cells stimulated by vagus nerve and gastrin
  • stimulation of H2 on parietal cells:
      • inc adenylyl cyclase, cAMP, PKA
      • Increased H+ (gastric acid)
  • ACh and gastrin also directly increase gastric acid secretion

Pharm:

  • reversible competitive H2 inhibitors on basolateral membrane of parietal cell (inverse agonist)
  • inhibit (basal/fasting/nocturnal) gastric acid secretion from parietal cells
  • reduce volume of gastric acid and its H+ conc

Pharmacokinetics:

  • rapidly absorbed following oral admin
  • small amounts of drugs undergo liver metab
  • excreted by kidneys

Side effects (low incidence except cimetidine):

  • diarrhea, headache, drowsiness
  • Less common: confusion, delirium, slurred speech–IV admin or in elderly
  • alter bioavailability bc inhibit gastric acid secretion

AEs:

  • Cimetidine inhibits P450 (ranitidine to less extent): prolong half-life of other drugs that are substrates for P450
  • long term use at high dose: decreased testosterone binding and inhibits CYP that hydroxylates estradiol
      • in men: gynecomastia, reduced sperm count, and impotence)

Tx:

  • uncomplicated Gastro-Esophageal Reflux Disease (GERD)***
  • promote healing of gastric and duodenal ulcers
  • prevent occurrence of stress ulcers
  • Zollinger-Ellison Syndrome: overproduction of gastrin (PPIs now preferred)
Comparison:
- same mech of action
- minimal side effects except cimetidine
- Potency:
Famotidine > Ranitidine > Cimetidine
62
Q

What treats GERD?

A

H2 antagonists

  • famotidine
  • ranitidine
  • cimetidine
63
Q

What does famotidine treat?

A

Tx:

  • uncomplicated Gastro-Esophageal Reflux Disease (GERD)***
  • promote healing of gastric and duodenal ulcers
  • prevent occurrence of stress ulcers
  • Zollinger-Ellison Syndrome: overproduction of gastrin (PPIs now preferred)
64
Q

What does ranitidine treat?

A

Tx:

  • uncomplicated Gastro-Esophageal Reflux Disease (GERD)***
  • promote healing of gastric and duodenal ulcers
  • prevent occurrence of stress ulcers
  • Zollinger-Ellison Syndrome: overproduction of gastrin (PPIs now preferred)
65
Q

What does cimetidine treat?

A

Tx:

  • uncomplicated Gastro-Esophageal Reflux Disease (GERD)***
  • promote healing of gastric and duodenal ulcers
  • prevent occurrence of stress ulcers
  • Zollinger-Ellison Syndrome: overproduction of gastrin (PPIs now preferred)

Inhibits CYP450 = side efects

Pharmacology Block 2 (12 decks)

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