Exam 2: Histamine

Question 1

Histamine formed by the action of ___ on ___.

Answer 1

Histamine decarboxylase

histidine

Question 2

The slowly turning over pool refers to…

Answer 2

histamine stored in granules in mast cells and basophils

Question 3

Histamine Release

Mechanisms

Answer 3

• Antigen-mediated
  
  • Ag binds to IgE-sensitized mast cell
• Non-antigen mediated
  
  • Induced by drugs, high MW proteins, venoms, and other process that disrupt cell membranes
  • May induce release by displacing histamine from storage granules

Question 4

Allergic reactions involve an antigen interacting with an ___.

Answer 4

IgE-sensitized mast cell

Question 5

Anaphylatoxic Drugs

Answer 5

• Morphine
• Codeine
• Curare ⇒ competitive Ach inhibitor
• Some neuromuscular blockers

Question 6

___ and ___ can contain polypeptides that cause histamine release.

Answer 6

Venom ⇒ basic polypeptides

Complement ⇒ C5a and C3a

Question 7

Stimulation of ___ inhibits release of histamine.

Answer 7

adrenergic β₂ receptors

(May be one mechanism of epinephrine in treating anaphylactic shock)

Question 8

Many effects of histamine mediated by…

Answer 8

histamine-1 receptor (H1)

Question 9

H1 Receptor

Transduction

Answer 9

G_q ⇒ IP₃ ⇒ ↑ [Ca²⁺]_{intracellular}

Question 10

Histamine

Effects

Answer 10

• Phosphorylation of myosin light chain
  
  • Smooth muscle contraction
    
    • Bronchoconstriction
• Production of NO
  
  • Vasodilation of post-capillary venules and arterioles
  • Engorgement of local microvasculature
    
    • Enhances diapedesis
    • Responsible for erythema
  • See some constriction of veins
  • Predominant systemic effect is hypotension
• Contraction of endothelial cells
  
  • Release of plasma proteins and fluids from post-capillary venules
  • Responsible for edema
• Depolarizes nerve endings
  
  • Sensation of itch and pain
  • Itching can be mediated by central mechanisms in some patients
• Stimulate NF𝜅B mediated transcription
  
  • Important in the immune response

Question 11

Histamine used as a ___ in allergy testing.

Answer 11

positive control

Question 12

The rapidly turning over pool is contained with…

Answer 12

enterochromaffin-like (ECL) cells

&

histaminergic neurons in CNS

Question 13

Histaminergic neurons originate in the ___ and project ___.

Answer 13

tuberomamillary nucleus

diffusely throughout the brain

Question 14

H2 Receptor

Transduction

Answer 14

G_s ⇒ cAMP

Question 15

The CNS activation of histamine may be responsible for…

Answer 15

wakefulness

Question 16

Histamine released from ECL cells acts via ___ to stimulate ___ by ___.

Answer 16

H2 receptors

stimulate acid secretion

Parietal cells

Question 17

Most H1 receptors appear to have ___ activity, ___ of histamine.

Answer 17

constitutive

independent

Question 18

Most histamine antagonists are ___.

Answer 18

inverse agonists

(Reduces constitutive activity of the receptor)

Question 19

First Generation

Antihistamines

Answer 19

• Diphenhydramine (Benadryl)
• Hydroxyzine (Atarax)
• Promethazine (Phenergan)
• Chlorpheniramine
• Dimenhydrinate (Dramamine)
• Meclizine (Motion relief)

Question 20

Second Generation

Antihistamines

Answer 20

• Fexofenadine
• Loratadine (Claritin)
• Cetirizine (Zyrtec)
• Desloratadine (Clarinex)

Question 21

Allergy Mechanism

Answer 21

Includes allergic rhinitis, acute urticaria, and pruritis.

• Ag crosses epithelium ⇒ underlying tissues
• Encounters previously sensitized mast cell
• Cross-linking of IgE/Fc receptor complex on mast cell
• Degranulation releasing histamine + inflammatory mediators
• Activation of H1 receptors
  
  • Vasodilation
  • ↑ vascular permeability

Question 22

Allergy Disorders

Treatment

Answer 22

• Antihistamines block edema caused by histamine
• Best used prophylactically
• Actions due in part to inhibition of NF𝜅B pathway
• 1st and 2nd generation antihistamines equally effective
  
  • 2nd gen preferred d/t better adverse effect profile
• Topical admin via nasal sprays and creams faster acting but requires more frequent administrations

Question 23

Pruritis

Treatment

Answer 23

• Antihistamines can be used for generalized itching
• In some cases, sx can originate from systemic abnormality
  
  • Ex. renal insufficiency
  • Successful treatment of underlying condition usually relieves itch
  • Antihistamines not effective here

Question 24

Motion Sickness

Treatment

Answer 24

• First generation antihistamines can be used
  
  • Dimenhydrinate
  • Meclizine
  • Promethazine
  • Diphenhydramine
• Some marketed as “less sedating” but all cause some sedation

Question 25

Insomnia Treatment

Answer 25

• First generation antihistamines can be used
  
  • Are not the preferred agents
• Also found in nighttime OTC meds

Question 26

Antihistamines

Excluded Conditions

Answer 26

• Are not used for:
  
  • Bronchial asthma
  • Anaphylaxis
  • Severe angioedema
• Because there are other mediators that contribute to disease
• Epinephrine is the drug of choice for anaphylaxis

Question 27

1st gen antihistamines are ___ at physiological pH and readily cross the ___.

Answer 27

neutral @ physiological pH ⇒ crosses BBB

Question 28

1st gen antihistamines are ___ and also block ____.

Answer 28

Less selective ⇒ blocks cholinergic, α-adrenergic and serotonergic receptors

Question 29

1st Gen Antihistamine

Adverse Effects

Answer 29

• Due to ⊗ cholinergic receptors
  
  • CNS depression
    
    • The elderly more susceptible to sedative effects
  • Blurred vision
  • Dry mouth
  • Urinary retention
• Due to ⊗ α-adrenergic receptors
  
  • Hypotension
  • Reflex tachycardia

Question 30

2nd gen antihistamines have a ___ structure and do not cross the ___.

Answer 30

amphoteric

BBB

Question 31

2nd gen antihistamines have improved ___, with less ___ activity.

Answer 31

H1 selectivity

anticholinergic

Question 32

Of 2nd gen antihistamines, ___ causes the most sedation.

Answer 32

cetirizine (Zyrtec)

Question 33

2nd Gen Antihistamines

Adverse Effects

Answer 33

• Sedation (milder)
• Dry mouth
• Headache
• Fatigue