Histamines

Question 1

Describe the synthesis and metabolism of Histamine

Answer 1

Histidine → Histamine → Imidazole → Imidazole acetate

Histidine → Histamine → N¹ methylhistamine → N¹-methylimidazole acetate

Enzyme from histidine to histamine: Histidine decarboxylase

Question 2

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

Answer 2

Histamine degrading enzymes

Question 3

Histamine Functions

Answer 3

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

Question 4

Localization of Histamine

Answer 4

Ubiquitous

• Highest amounts in lung, skin, GI tract

Question 5

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

Answer 5

• 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

Question 6

Characteristics of histamine from non-mast cells

Answer 6

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

Question 7

Effects of histamine release (within seconds? minutes?)

Answer 7

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

Question 8

Explain the release of mast cell histamine

Answer 8

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

Question 9

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

Answer 9

Drugs: Succinylcholine, morphine…

Peptides: Bradykinin, complement, substance P

Venoms: Wasps

* mechanism of release is through an increase in intracellular calcium

Question 10

Red-Man Syndrome

Answer 10

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

Question 11

Other stimuli that release histamine

Answer 11

• Cold Urticaria
• Cholinergic Urticaria
• Solar Urticaria

* Urticaria = hives

Question 12

Cromolyn sodium

Administration:

Mechanism:

Side Effects:

Answer 12

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

Question 13

Cromolyn sodium therapeutic uses

Answer 13

• 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)

Question 14

Omalizumab (Monoclonal antibody)

Administration:

Mechanism of Action:

Answer 14

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

Question 15

G Protein Coupling and Distribution of Histamine Receptors

H1:

H2:

H3:

H4:

Answer 15

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

Question 16

Representative antagonists for H1 and H2

Answer 16

H1: Chlorpheniramine

H2: Ranitidine

Question 17

Histamine receptors that induce vasodilation

Answer 17

H1 (endothelial cells) - ↑NO = vasodilation

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

Question 18

Histamine Receptors and Vasoconstriction of large vessels

Answer 18

H1 receptors located on vascular smooth muscle cells

• Increase intracellular calcium

Question 19

Histamine Receptors and Blood Pressure

Answer 19

Both H1 and H2 receptors

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

Question 20

Histamine Receptors and Increased vascular permeability

Answer 20

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

Question 21

Histamine Receptors and Effects on Heart

Answer 21

Predominantly H2 receptors

• Contractlity increased
• Increase electrical conduction

Question 22

Histamine Receptors and Bronchioles

Answer 22

H1: contraction

H2: relaxation (minor)

Question 23

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

Answer 23

Intestinal Smooth Muscle: H1 - contraction

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

Peripheral Nerve Endings: H1 - pain and itching

Question 24

Neuroendocrine Effects of Histamine Receptors

Increasing Arousal/wakefullness:

Answer 24

H1 (in the brain)

Question 25

H1 receptor blockers ## Footnote First Generation: Second Generation:

Answer 25

First Generation: * Diphenhydramine * Dimenhydrinate * Chlorpheniramine * Promethazine Second Generation * Fexofenadine * Loratadine * Cetirizine * Desloratidine

Question 26

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

Answer 26

Inverse agonists

Question 27

Major pharmacologic Effect of H1 antagonists

Answer 27

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

Question 28

Major pharmacologic effects of H1 Antagonists ## Footnote CNS: Peripheral and central anticholinergic effect: Local Anisthetic Effect:

Answer 28

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

Question 29

H1 receptor Drugs ## Footnote Administration: Distribution: Metabolism:

Answer 29

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**

Question 30

Sedation is most common with __________ drugs due to inhibition of central H1 effect AND central cholinergic effect 2nd generation with most sedative effect is \_\_\_\_\_\_

Answer 30

1st generation Cetirizine

Question 31

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

Answer 31

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

Question 32

GI side effects of drugs

Answer 32

Loss of appetite, nausea, vomiting

Question 33

Major Cardiovascular Toxicity due to _________ drugs \_\_\_\_\_\_\_\_ is metabolized by P450 and has never shown adverse effects on QT interval; no cardiac toxicity

Answer 33

2nd generation Loratadine

Question 34

Drugs used to treat allergies First genaration: Second Genearation: \_\_\_\_\_\_\* is the first generation with most sedative effect

Answer 34

First Gen: * Diphenhydramine\* * Chlorpheniramine Second Gen: * Fexofenadine * Loratadine * Desloratadine * Cetirizine

Question 35

Motion sickness Definition: Drugs:

Answer 35

Definition: A temporary condition that involves dizziness, nausea, and vomiting Drugs: Anti cholinergic effect: * Dimenhydrinate * Promethazine * Diphenhydramine * (Scopolamine)

Question 36

Drugs for... ## Footnote Non-prescription sleeping tablets: Vestibular disturbances: Chemotherapy-induced nausea and vomiting: Early stage Parkinson's disease:

Answer 36

Non-prescription sleeping tablets: Diphenhydramine Vestibular disturbances: Dimenhydrinate Chemotherapy-induced nausea and vomiting: Promethazine Early stage Parkinson's disease: Diphenhydramine

Question 37

Function of H2 receptor antagonists

Answer 37

* 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

Question 38

Physiology of Gastric Acid secretion (H2 receptors)

Answer 38

* 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

Question 39

Pharmacological Profile of H2 Antagonists

Answer 39

* 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

Question 40

H2 Antagonists ## Footnote Administration: Metabolism: Excretion:

Answer 40

Administration: Oral administration - rapid Metabolism: Small amounts undergo liver metabolism Excretion: Kidney

Question 41

H2 Antagonists Adverse Effects

Answer 41

* 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

Question 42

Adverse effects of Cimetidine

Answer 42

Inhibits P450 metabolism * Prolongs half-life of other drugs Long term use: * Decreased testosterone binding * Inhibition of CYP enzme that hydroxylates estradiol

Question 43

Major Use of H2 Antagonists

Answer 43

Uncomplicated Gastro-Esophageal Reflux Disease (GERD) * Promote healing of ulcers * Prevent occurence of ulcers

Question 44

H2 Antagonist Potency

Answer 44

Famotidine \> Nizatidine = Ranitidine \> Cimetidine