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Pharm Block 2 > Lecture 6: Histamine > Flashcards

Lecture 6: Histamine Flashcards

1
Q

H1 Blockers

A 
Diphenhydramine
Dimenhydrinate 
Chlorpheniramine
Promethazine
Fexofenadine
Loratadine
Desloratadine
Cetirizine
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2
Q

H2 Blockers

A

Cimetidine
Ranitidine
Famotidine

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3
Q

Other

A

Cromolyn sodium

Omalizumab

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4
Q

Major pharmacologic effect of H1 antagonists

A
  1. By blocking histamine receptors on vascular tissue, reduce the symptoms associated with allergic responses/inflammation
    a. ) inhibition of vascular permeability
    b. ) suppress itching
    c. .) No effect on BP or bronchoconstriction
  2. CNS
    a. ) 1st generation and sedation
    b. ) 1st generation and stimulation in children
    c. ) 1st generation and motion sickness (CNS anti-cholinergic effect)
  3. Peripheral and central anticholinergic effect seen with many 1st generation drugs
    a. ) Atropine-like effects
    b. ) Dry mucus membranes
    c. ) Urinary retention
    d. ) think about anticholinergic syndrome
  4. Local anesthetic effect
    a. ) Block nerve conduction
    b. ) Seen with some 1st generation at high dose like PROMETHAZINE
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5
Q

Diphenhydramine

A

1st generation with most sedative effect

Uses: Allergies, Motion sickness, Sleeping, Early stage Parkinson’s disease

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6
Q

Dimenhydrinate

A

1st generation

Uses: Allergies, Motion sickness, Vestibular disturbances

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7
Q

Chlorpheniramine

A

1st generation

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8
Q

Promethazine

A

1st generation

Uses: Allergies, Motion sickness, Chemotherapy induced nausea and vomiting

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9
Q

Fexofenadine

A

2nd generation

NOT metabolized by P450

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10
Q

Loratadine

A

2nd generation

Metabolized by CYP450 to desloratadine

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11
Q

Cetirizine

A

2nd generation with most sedative effect

Active metabolite of hydroxyzine

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12
Q

Cimetidine

A

H2 receptor antagonist

Has the most potential for adverse effect due to inhibiting P450 metabolism

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13
Q

Famotidine

A

H2 receptor antagonist

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14
Q

Ranitidine

A

H2 receptor antagonist

Also inhibits P450 metabolism but to less of an extent than Cimetidine

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15
Q

Cromolyn sodium

A

Mechanism: Stabilizes mast cell membrane to prevent release of histamine.

Uses:
Chronic control of asthma and prophylaxis of bronchospasm (allergen or exercise induced). NOT A RESCUE MEDICINE
Nasal formulation for allergies
Opthalmic formulation for conjunctivitis
Oral formulation for systemic mastocytosis (significant increases in mast cell numbers in the skin and internal organs)
Off label uses for food allergy and irritable bowel syndrome

SE: Safe drug/few side effects

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16
Q

Omalizumab

A

Mechanism: IgG monoclonal antibody for which the antigen is the Fc region of the IgE antibody. Forms omalizumab-IgE complexes ergo no affinity for FcRI

Uses: Decreases amount of antigen specific IgE that normally binds to and sensitizes mast cells,

SE: Injection site reaction, anaphylaxis after the first dose and in some cases >1 year after initiation of regular treatment.

17
Q

Synthesis of histamine

A

L-histidine converted to histamine by histidine decarboxylase (an inducible enzyme with PLP) which is inhibited by methylhistidine.

18
Q

Storage of histamine

A 
(Mostly found in lung, skin, GI).  
Synthesized and stored in secretory granules in inactive form bound to proteoglycans.
Heparin-sulfate+ATP: mast cells: tissues
Chondroitin sulfate: basophils: blood
Slow turn over
Non-mast cells (gastric mucosa, epidermis, neurons): continuously synthesized and released
Rapid turnover (activity dependent on histidine decarboxylase activity)
19
Q

Effects of histamine release

A 
Within seconds:
Burning, itching sensation
Intense warmth
Skin reddens
BP decreases
HR increases

Within minutes:
BP recovers
Hives appear

20
Q

Release of histamine

A
  1. Antigen-antibody reaction:
    Prior exposure (induction of IgE mediated allergic sensitivyt to drugs and other allergens, response of IgE-sensitized cells to subsequent exposure to allergens)
    Calcium-dependent
    Releases other mediators as well
  2. Drugs, peptides, venoms that promote release
    Drugs: succinylcholine, morphine, curare, antibiotics like VANCOMYCIN INDUCED RED MAN SYNDROME
    Peptides: Bradykinin, complement, substance P=released during tissue injury
    Venoms: wasp venom
    *Mechanism of release is through an increase in intracellular calcium
21
Q

Red man/red neck/red person syndrome

A

Caused by vancomycin (used for serious gram positive bacteria, a last resort antibiotic,)
Following rapid IV infusion
Rash in face, neck, upper torso
Hypotension
Due to mas cell degranulation (not allergic rxn to vancomycin)
Some evidence that altered histamine metabolism contributes to the pathogenesis

22
Q

Other stimuli that release histamine

A

Cold urticaria
Cholinergic urticaria (increased sympathetic nervous activity w exercise and stress stimulates cholinergic fibers innervating sweat glands to release acetylcholine, leading to mast cell degranulation)
Solar urticaria
Nonspecific cell damage

23
Q

Identify the major classes of histamine receptors - H1, H2 (with mention of H3 and H4) and explain their tissue distribution and function.

A

All GPCRs.
Only H1 and H2 are therapeutically targeted.
These two use diff secondary messengers, H1 uses increase in Ca2+ whereas H2 uses increase in cAMP

24
Q

Define the principal adverse effects of the H1 and H2 receptor antagonists.

A

Sedation from 1st generation inhibition of central H1 mediating arousal AND central cholinergic receptors.
2nd generation with most sedation is CETIRIZINE. Remember PARADOXICAL EXCITATION IN CHILDREN

GI side effects (minor): loss of appetite, nausea, vomiting.
However in rare case, increased appetite and weight gain due to an H1 central effect to decrease appetite

Other anticholinergic side effects:
Peripheral muscarinic receptors
Seen only with some 1st generation drugs
Dry mouth, dryness of respiratory passages, urinary retention

Major CV toxicity in early second generation due to CYP450 metabolized.
Loratadine never resulted in adverse effects on CV.

25
Q

What systems are affected by histamine

A
  1. CV
  2. Non-vascular smooth muscle:
    a.)Bronchioles: MINOR but,
    H1: contraction, H2: relaxation.
    b.)Intestinal smooth muscle: H1-contraction
  3. Exocrine glands:
    H2-gastric secretion in GI secretory tissue
  4. Peripheral nerve endings:
    H1- pain and itching
  5. Neuroendocrine effects:
    H1-arousal and decrease appetite
26
Q

CV effects through histamine

A
  1. Vasodilation:
    H1 increases intracellular calcium and activates Nitric oxide synthase in endothelial cells
    H2 increases cAMP in vascular smooth muscle cells, decreasing Ca2+ and decreasing rate of myosin phosphorylation
  2. Vasoconstriction:
    H1 receptors on vascular smooth muscle cells results in increase in intracellular calcium.
  3. Blood pressure:
    Both H1 and H2 receptors
    Histamine dilates resistance vessels and causes an overall fall in BP
  4. Increased vascular permeability:
    H1 receptors on postcapillary venules causes endothelial cells to contract. This exposes the basement membrane which is freely permeable to plasma protein and fluid.
  5. Heart: Affects both cardiac contractility and electrical events directly, predominantly H2
27
Q

Differences between 1st and 2nd generation histamine blockers

A

2nd generation does not enter brain
Some 2nd generation is metabolized by P450 enzymes (CYP3A4/CYP2D6)
a.) Fexofenadine is NOT
b.) Loratidine is metabolized to desloratadine
c. Cetirizine is active metabolite of hydroxyzine

28
Q

Clinical uses for H1 blockers

A

Acute types of allergies for seasonal, but not as effective when allergic response already started (b/c competitive antagonists) 1. Allergens abundant. 2. Exposure prolonged. 3. Nasal decongestant prominent

Motion sickness (involves muscarinic cholinergic transmission). To treat need anti-cholinergic effect
Dimenhydrinate
Promethazine
Diphenhydramine
*but usually scopolamine a muscarinic receptor antagonist is used

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

29
Q

Mechanism of H2 receptor antagonists

A

Normally histamine released from mast cells and enterochromaffin like cells. Stimulates H2 receptors on parietal cells, increases adenyl cyclase, cAMP, PKA, resulting in increase in acid. (SO CAN GASTRIN AND ACETYLCHOLINE)

30
Q

Adverse effects of H2 receptor antagonists

A

Generally low EXCEPT FOR CIMETIDINE (inhibits P450 metabolism), so can ranitidine but to less of an extent.
Decreased testosterone binding due to Inhibition of CYP enzyme that hydroxylates estradiol. Thus in men see gynecomastia, reduced sperm count, and impotence.

Recommended 2nd generation for Elderly because of serious CNS effects.

Alters bioavailability of other drugs through change in pH

31
Q

Major Use of H2 receptor antagonists

A

Treat GERD (gastro esophageal reflux disease), promotes healing of gastric and duodenal ulcers.

Previously usd to treat Zollinger=Ellison syndrome (non beta cell tumor of pancrease, overproduction of gastrin). Now protein pump inhibitors are preferred.

Pharm Block 2 (14 decks)

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