Histamines Flashcards
Describe the synthesis and metabolism of Histamine
Histidine → Histamine → Imidazole → Imidazole acetate
Histidine → Histamine → N1 methylhistamine → N1-methylimidazole acetate
Enzyme from histidine to histamine: Histidine decarboxylase
Alterations in ______ ______ _______ can account for histamine intolerance (1% population)
Histamine degrading enzymes
Histamine Functions
- Mediator of immediate allergic and inflammatory reactions
- Role in gastric acid secretion
- Neurotransmitter and neuromodulator
Localization of Histamine
Ubiquitous
- Highest amounts in lung, skin, GI tract
Characteristics of histamine in tissues (mast cells) and in blood (basophils)
- 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
Characteristics of histamine from non-mast cells
- No granules, continuously synthesized and released, rapid turnover
- Histidine decarboxylase levels correlate with activity
Effects of histamine release (within seconds? minutes?)
- Within seconds
- Burning, itching
- Intense warmth
- Skin reddens
- BP ↓
- HR ↑
- Within Minutes
- BP recovers
- Hives
Explain the release of mast cell histamine
- Antigen-antibody reaction
- IgE mediated sensitivity to drugs and other allergens
- Response of IgE sensitized cells to subsequent exposure to allergens
- Ca2+ dependent
Drugs, Venoms, and peptides can promote the release of histamine - what are some examples of each?
Drugs: Succinylcholine, morphine…
Peptides: Bradykinin, complement, substance P
Venoms: Wasps
* mechanism of release is through an increase in intracellular calcium
Red-Man Syndrome
- Caused by vancomycin interaction w/ gram-positive bacteria
- Due to mast cell degranulation
- Rash in face, neck, upper torso
- Following rapid IV infusion
Other stimuli that release histamine
- Cold Urticaria
- Cholinergic Urticaria
- Solar Urticaria
* Urticaria = hives
Cromolyn sodium
Administration:
Mechanism:
Side Effects:
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
Cromolyn sodium therapeutic uses
- 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)
Omalizumab (Monoclonal antibody)
Administration:
Mechanism of Action:
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
G Protein Coupling and Distribution of Histamine Receptors
H1:
H2:
H3:
H4:
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
Representative antagonists for H1 and H2
H1: Chlorpheniramine
H2: Ranitidine
Histamine receptors that induce vasodilation
H1 (endothelial cells) - ↑NO = vasodilation
H2 (vascular smooth muscle cells) - increase cAMP so decrease intracellular calcium
Histamine Receptors and Vasoconstriction of large vessels
H1 receptors located on vascular smooth muscle cells
- Increase intracellular calcium
Histamine Receptors and Blood Pressure
Both H1 and H2 receptors
- In general histamine dilates resistance vessels and causes an overall fall in BP
Histamine Receptors and Increased vascular permeability
- H1 receptors located on post-capillary venules- endothelial cells
- Increase in Ca2+ causes endothelial cells to contract and expose basement membrane
Histamine Receptors and Effects on Heart
Predominantly H2 receptors
- Contractlity increased
- Increase electrical conduction
Histamine Receptors and Bronchioles
H1: contraction
H2: relaxation (minor)
Histamine Receptor activation of Intestinal Smooth muscle, Exocrine Glands and Peripheral nerve endings
Intestinal Smooth Muscle: H1 - contraction
Exocrine Glands (Parietal Cell): H2 - gastric acid secretion
Peripheral Nerve Endings: H1 - pain and itching
Neuroendocrine Effects of Histamine Receptors
Increasing Arousal/wakefullness:
H1 (in the brain)
H1 receptor blockers
First Generation:
Second Generation:
First Generation:
- Diphenhydramine
- Dimenhydrinate
- Chlorpheniramine
- Promethazine
Second Generation
- Fexofenadine
- Loratadine
- Cetirizine
- Desloratidine
Histamine Receptor drugs are considered _____ _______ because they reduce constitutive activity at receptors and compete with histamine
Inverse agonists
Major pharmacologic Effect of H1 antagonists
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
Major pharmacologic effects of H1 Antagonists
CNS:
Peripheral and central anticholinergic effect:
Local Anisthetic Effect:
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
H1 receptor Drugs
Administration:
Distribution:
Metabolism:
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
Sedation is most common with __________ drugs due to inhibition of central H1 effect AND central cholinergic effect
2nd generation with most sedative effect is ______
1st generation
Cetirizine
Give 2 reasons that 1st generation antihistamines have a sedative effect
- Enter CNS and block H1 receptors that mediate arousal
- Non-specific and also have structures that allow them to block cholinergic receptors in CNS
GI side effects of drugs
Loss of appetite, nausea, vomiting
Major Cardiovascular Toxicity due to _________ drugs
________ is metabolized by P450 and has never shown adverse effects on QT interval; no cardiac toxicity
2nd generation
Loratadine
Drugs used to treat allergies
First genaration:
Second Genearation:
______* is the first generation with most sedative effect
First Gen:
- Diphenhydramine*
- Chlorpheniramine
Second Gen:
- Fexofenadine
- Loratadine
- Desloratadine
- Cetirizine
Motion sickness
Definition:
Drugs:
Definition: A temporary condition that involves dizziness, nausea, and vomiting
Drugs: Anti cholinergic effect:
- Dimenhydrinate
- Promethazine
- Diphenhydramine
- (Scopolamine)
Drugs for…
Non-prescription sleeping tablets:
Vestibular disturbances:
Chemotherapy-induced nausea and vomiting:
Early stage Parkinson’s disease:
Non-prescription sleeping tablets: Diphenhydramine
Vestibular disturbances: Dimenhydrinate
Chemotherapy-induced nausea and vomiting: Promethazine
Early stage Parkinson’s disease: Diphenhydramine
Function of H2 receptor antagonists
- 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
Physiology of Gastric Acid secretion (H2 receptors)
- 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
Pharmacological Profile of H2 Antagonists
- 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
H2 Antagonists
Administration:
Metabolism:
Excretion:
Administration: Oral administration - rapid
Metabolism: Small amounts undergo liver metabolism
Excretion: Kidney
H2 Antagonists Adverse Effects
- 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
Adverse effects of Cimetidine
Inhibits P450 metabolism
- Prolongs half-life of other drugs
Long term use:
- Decreased testosterone binding
- Inhibition of CYP enzme that hydroxylates estradiol
Major Use of H2 Antagonists
Uncomplicated Gastro-Esophageal Reflux Disease (GERD)
- Promote healing of ulcers
- Prevent occurence of ulcers
H2 Antagonist Potency
Famotidine > Nizatidine = Ranitidine > Cimetidine
