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PDA Block 2 > Histamines > Flashcards

Histamines Flashcards

1
Q

Describe the synthesis and metabolism of Histamine

A

Histidine → Histamine → Imidazole → Imidazole acetate

Histidine → Histamine → N1 methylhistamine → N1-methylimidazole acetate

Enzyme from histidine to histamine: Histidine decarboxylase

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2
Q

Alterations in ______ ______ _______ can account for histamine intolerance (1% population)

A

Histamine degrading enzymes

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3
Q

Histamine Functions

A
  • Mediator of immediate allergic and inflammatory reactions
  • Role in gastric acid secretion
  • Neurotransmitter and neuromodulator
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4
Q

Localization of Histamine

A

Ubiquitous

  • Highest amounts in lung, skin, GI tract
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5
Q

Characteristics of histamine in tissues (mast cells) and in blood (basophils)

A
  • Synthesized and stored in secretory granules in an inactive form
  • Bound to a proteoglycan
    • Heparin sulfate and ATP: mast cells
    • Chondroitin-sulfate: basophils
  • Slow turnover
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6
Q

Characteristics of histamine from non-mast cells

A
  • No granules, continuously synthesized and released, rapid turnover
  • Histidine decarboxylase levels correlate with activity
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7
Q

Effects of histamine release (within seconds? minutes?)

A
  • Within seconds
    • Burning, itching
    • Intense warmth
    • Skin reddens
    • BP ↓
    • HR ↑
  • Within Minutes
    • BP recovers
    • Hives
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8
Q

Explain the release of mast cell histamine

A
  • Antigen-antibody reaction
    • IgE mediated sensitivity to drugs and other allergens
    • Response of IgE sensitized cells to subsequent exposure to allergens
  • Ca2+ dependent
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9
Q

Drugs, Venoms, and peptides can promote the release of histamine - what are some examples of each?

A

Drugs: Succinylcholine, morphine…

Peptides: Bradykinin, complement, substance P

Venoms: Wasps

* mechanism of release is through an increase in intracellular calcium

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10
Q

Red-Man Syndrome

A
  • Caused by vancomycin interaction w/ gram-positive bacteria
  • Due to mast cell degranulation
  • Rash in face, neck, upper torso
  • Following rapid IV infusion
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11
Q

Other stimuli that release histamine

A
  • Cold Urticaria
  • Cholinergic Urticaria
  • Solar Urticaria

* Urticaria = hives

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12
Q

Cromolyn sodium

Administration:

Mechanism:

Side Effects:

A

Administration: Inhalation (oral, nasal, opthalmic possible)

Mechanism: Stabilizes mast cell membrane to prevent release of histamine - exact cellular mechanism is unclear

Side Effects: Safe drug/ few side effects

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13
Q

Cromolyn sodium therapeutic uses

A
  • Chronic control of asthma
  • Prophylaxis of bronchospasm (NOT A RESCUE MED)
  • Nasal formulation for allergies
  • Opthalmic for conjuctivitis
  • Oral for systemic mastocycosis
  • Off label use for food allergy and IBS (irritable bowel)
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14
Q

Omalizumab (Monoclonal antibody)

Administration:

Mechanism of Action:

A

Administration: Subcutaneous

Mechanism of Action:

  • Decrease amount of IgE that normally binds to mast cells
  • An IgG antibody for which antigen is Fc region of IgE
  • Binds tightly to free IgE in circulation to form complex
  • No affinity for FcRI
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15
Q

G Protein Coupling and Distribution of Histamine Receptors

H1:

H2:

H3:

H4:

A

H1:

  • G Protein: Gq (Ca2+, ↑ NO and ↑ cGMP)
  • Dist: Smooth muscle, endothelial cells, CNS

H2:

  • G Protein: Gs (↑ cAMP)
  • Dist: Gastric parietal cells, cardiac muscle, mast cells, CNS

H3:

  • G Protein: Gi ( ↓ cAMP; ↑ MAP)
  • Dist: CNS: presynaptic

H4:

  • G Protein: Gi ( ↓ cAMP; ↑ Ca2+)
  • Dist: Cells of hematopoietic origin
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16
Q

Representative antagonists for H1 and H2

A

H1: Chlorpheniramine

H2: Ranitidine

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17
Q

Histamine receptors that induce vasodilation

A

H1 (endothelial cells) - ↑NO = vasodilation

H2 (vascular smooth muscle cells) - increase cAMP so decrease intracellular calcium

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18
Q

Histamine Receptors and Vasoconstriction of large vessels

A

H1 receptors located on vascular smooth muscle cells

  • Increase intracellular calcium
19
Q

Histamine Receptors and Blood Pressure

A

Both H1 and H2 receptors

  • In general histamine dilates resistance vessels and causes an overall fall in BP
20
Q

Histamine Receptors and Increased vascular permeability

A
  • H1 receptors located on post-capillary venules- endothelial cells
    • Increase in Ca2+ causes endothelial cells to contract and expose basement membrane
21
Q

Histamine Receptors and Effects on Heart

A

Predominantly H2 receptors

  • Contractlity increased
  • Increase electrical conduction
22
Q

Histamine Receptors and Bronchioles

A

H1: contraction

H2: relaxation (minor)

23
Q

Histamine Receptor activation of Intestinal Smooth muscle, Exocrine Glands and Peripheral nerve endings

A

Intestinal Smooth Muscle: H1 - contraction

Exocrine Glands (Parietal Cell): H2 - gastric acid secretion

Peripheral Nerve Endings: H1 - pain and itching

24
Q

Neuroendocrine Effects of Histamine Receptors

Increasing Arousal/wakefullness:

A

H1 (in the brain)

25
Q

H1 receptor blockers

First Generation:

Second Generation:

A

First Generation:

  • Diphenhydramine
  • Dimenhydrinate
  • Chlorpheniramine
  • Promethazine

Second Generation

  • Fexofenadine
  • Loratadine
  • Cetirizine
  • Desloratidine
26
Q

Histamine Receptor drugs are considered _____ _______ because they reduce constitutive activity at receptors and compete with histamine

A

Inverse agonists

27
Q

Major pharmacologic Effect of H1 antagonists

A

By blocking histamine receptors on vascular tissue, reduce the symptoms associated with allergic responses/inflammation

  • Inhibition of vascular permeability
  • Suppress itching
  • No effect on BP or bronchoconstriction
28
Q

Major pharmacologic effects of H1 Antagonists

CNS:

Peripheral and central anticholinergic effect:

Local Anisthetic Effect:

A

CNS: 1st generation

  • Sedation (most common)
  • Stimulation (children)
  • Motion sickness (anticholinergic effect)

Peripheral and central anticholinergic effect: 1st generation

  • Dry mucus membranes
  • Urinary retention

Local Anisthetic Effect: block nerve conduction

29
Q

H1 receptor Drugs

Administration:

Distribution:

Metabolism:

A

Administration: Oral (topical, nasal possible) - rapid absorption

Distribution: widely distributed - 2nd generation less likely to enter brain

Metabolism: Liver

  • 2nd generation metabolized by P450 enzymes
  • Terfenadine → fexofenadine
  • Loratadine → Desloratadine
  • Hydroxyzine → Cetirizine
30
Q

Sedation is most common with __________ drugs due to inhibition of central H1 effect AND central cholinergic effect

2nd generation with most sedative effect is ______

A

1st generation

Cetirizine

31
Q

Give 2 reasons that 1st generation antihistamines have a sedative effect

A
  1. Enter CNS and block H1 receptors that mediate arousal
  2. Non-specific and also have structures that allow them to block cholinergic receptors in CNS
32
Q

GI side effects of drugs

A

Loss of appetite, nausea, vomiting

33
Q

Major Cardiovascular Toxicity due to _________ drugs

________ is metabolized by P450 and has never shown adverse effects on QT interval; no cardiac toxicity

A

2nd generation

Loratadine

34
Q

Drugs used to treat allergies

First genaration:

Second Genearation:

______* is the first generation with most sedative effect

A

First Gen:

  • Diphenhydramine*
  • Chlorpheniramine

Second Gen:

  • Fexofenadine
  • Loratadine
  • Desloratadine
  • Cetirizine
35
Q

Motion sickness

Definition:

Drugs:

A

Definition: A temporary condition that involves dizziness, nausea, and vomiting

Drugs: Anti cholinergic effect:

  • Dimenhydrinate
  • Promethazine
  • Diphenhydramine
  • (Scopolamine)
36
Q

Drugs for…

Non-prescription sleeping tablets:

Vestibular disturbances:

Chemotherapy-induced nausea and vomiting:

Early stage Parkinson’s disease:

A

Non-prescription sleeping tablets: Diphenhydramine

Vestibular disturbances: Dimenhydrinate

Chemotherapy-induced nausea and vomiting: Promethazine

Early stage Parkinson’s disease: Diphenhydramine

37
Q

Function of H2 receptor antagonists

A
  • Relief from symptoms of peptic ulcer disease
  • Gastroesophageal reflux disease
  • Peptic ulcer secondary to Helicobacter pylori infection
  • Gastric injury caused by nonsteroidal anti-inflammatory drugs
38
Q

Physiology of Gastric Acid secretion (H2 receptors)

A
  • Histamine released from mast cells and enterochromaffin-like cells (vagus stimulation)
  • Stimulation of H2 receptors on parietal cells increase cAMP and PKA
    • Cause increase in Acid (H+)

* ACH and gastrin also have direct effect on parietal cells to release acid

39
Q

Pharmacological Profile of H2 Antagonists

A
  • Reversible competitive inhibitors
    • Act as inverse agonists
    • Specific for H2 receptors on basolateral membrane of parietal cells
  • Inhibit basal (fasting) gastric acid secretion
  • Inhibit nocturnal gastric acid secretion
  • Reduce volume of gastric acid and H+concentration
40
Q

H2 Antagonists

Administration:

Metabolism:

Excretion:

A

Administration: Oral administration - rapid

Metabolism: Small amounts undergo liver metabolism

Excretion: Kidney

41
Q

H2 Antagonists Adverse Effects

A
  • Incidence relatively low - except for cimetidine
  • More common minor side effects - diarrhea, headaches, drowsiness
  • Less common
    • CNS effects of confusion, delirium, slurred speech
    • Happens with IV administration or in elderly patients
42
Q

Adverse effects of Cimetidine

A

Inhibits P450 metabolism

  • Prolongs half-life of other drugs

Long term use:

  • Decreased testosterone binding
  • Inhibition of CYP enzme that hydroxylates estradiol
43
Q

Major Use of H2 Antagonists

A

Uncomplicated Gastro-Esophageal Reflux Disease (GERD)

  • Promote healing of ulcers
  • Prevent occurence of ulcers
44
Q

H2 Antagonist Potency

A

Famotidine > Nizatidine = Ranitidine > Cimetidine

PDA Block 2 (15 decks)

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