Antihistamines Flashcards
What are the 2 First Generation Antihistamines
Chlorpheniramine, Diphenhydramine
What are the 2 Second Generation Antihistamines
Cetirizine, Fexofenadine
How is Histamine synthesised?
Histidine decarboxylase catalyses the conversion of Histidine to Histamine, with the release of CO2
What are the Histamine Metabolisers?
1) Histamine N-methyltransferase
2) Diamine oxidase
3) Monoamine Oxidase
What are the ceullular sources of histamine?
1) Mast Cells
2) Basophils
3) ECL Cells
4) Histaminergic neurons
How are Anti-Histamines Released?
Mast Cell Degranulation: IgE Mediated Allergy
1) Mast cells with IgE bound on surface
2) Allergen binding cross links IgE
3) Mediators released
What are the Biological actions of Histamine?
9 Actions
1) Smooth Muscle Contraction
2) Vasodilation
3) Increased Vascular Permeability
4) Immediate Symptoms of Wheel-Flare
5) Sensory Neuron to mediate pain and itch
6) Increase release of histamine and other mediators from mast cells and basophils
7) Stimulate gastric acid secretion (x)
8) Modulation of histaminergic neurotransmission
9) Immunodilation
What are the effects of Histamine on Smooth Muscle?
Contraction of smooth muscles (Bronchial, Intestinal)
What are the effects of Histamine on Blood Vessels?
Vasodilation - Endothelium produced Nitric Oxide
Increased Vascular Permeability - contraction of endothelial barrier and increase gap junction
What are the effects of Histamine on skin?
Immediate Wheal (swelling - vascular permeabilty) and Flare (redness - Vasodilation) reaction
What are the effects of Histamine on mast cells and basophils?
Increased release of histamine and other mediators
What are the effects of Histamine on neurons?
Modulates histaminergic neurotransmissions, affecting sleep/wake cycle, arousal, alertness, attention, cognition, learning and memory
What are the effects of Histamine on Immune system?
Immunomodulation
What type of Receptor are Histamine Receptors?
GPCR
What are H1 receptors and what is the Signalling Pathway?
H1 receptors are for acute allergic reactions
1) Gaq/11 activates PLCb (phospholipase C beta)
2) converts PIP2 to Diacyl Glycerol and Inositol triphosphate
3) DG activates Protein kinase C, IP3 causes release of Ca2+
4) Nitric oxide and Arachidonic Acid also increase
What are H1-Antihistamines?
Inverse Agonist
What is the mechanism of action of H1-Antihistamines?
H1 receptors are constitutively active, with inactive and active receptors in equilibrium
- Histamine stabilises H1 receptors in active form
- Antihistamines stabilise H1 recpetors in inactive form
Reduces basal level of activity
inhibit H1 Receptor
NOT COMPETITIVE ANTAGONIST
What are the clinical uses for Antihistamines?
1st Gen - Non-Allergic conditions
2ns Gen - Mild-moderate allergy
What are the clinical uses of 1 Generation Antihistamines?
Sedating - Non Allergic Conditions (used for its adverse drug reactions)
Motion sickness/vertigo, nauseu/vomiting, insomnia and peri operations (DIPHENHYDRAMINE)
What are the clinical uses of 2nd Generation Antihistamines?
Non-Sedating - Mild moderate allergies
Allergic rhinitis, Allergic Conjunctivitis, Allergic Urticaria (hives), Food Allergy, Mastocytosis
What are the conditions treated with H1-Antihistamines that have strong evidence base?
Second generation: Allergic Rhinitis, Allergic Cojunctivitis, Allergic Urticaria
What are the conditions treated with H1-Antihistamines that have weak evidence base?
URTI, Sinusitis, non-specific cough
What are the conditions treated with FIRST GENERATION H1 antihistamine that have weak evidence base?
Insomnia, Perioperative Sedation, Motion Sickness, vertigo
What is mechanism of Antihistamines?
antihistamine will bind and block H1 Receptor
Decrease Vasodilation
Decrease Vascular Permeability
Decrease Wheal and flare
Reduce Itch
Block Gaq (GPCR)
Reduce Calcium Level, stabilise Mast cells and decrease mediator release
Reduce PKC (long term effect) - modulation of gene transcription and gene translation, reduce expression of proinflammatory
What is the effect of Antihistamines on H1 Receptor?
Blockage, resultign in decrease vasodilation, vascular permeability, wheal and flare and itch
What is the effect of Antihistamines on Gaq?
Blockage, resulting in decrease calcium levels -> stabilising mast cells and decrease mediator release
Long Term effect: Reduce Protein kinase C -> modulation of gene expression, reduce expression of proinflammatory
Differences between 1st and 2nd Generation
1st vs 2nd
1) Sedating vs Non-Sedating
2) Low vs High H1-receptor Specificity
3) Anti- Muscarnic, Anti- Adrenergic, Anti-hydroxytryptaminergic vs NIL
4) highly vs Less Lipophillic
5) Low MW vs high MW
6) Readily vs Less Readily Pass BBB
7) Lack interaction vs High affinity for P glycoprotein efflux pump (pump out of brain)
8) High vs Low CNS H1 receptor Occupancy (fexo 0% cetiri 30%)
9) 2-3hr vs 1-2hr Onset of Action
10) 12hr vs 24hr Duration
What are the receptors in which side effect form 1st generation antihistamines derive from?
CNS H1 receptor, Muscarinic, Serotonin receptors, a-adrenergic receptors, Cardiac ion channels
What are the side effects of 1st Gen Antihistamines on CNS H1?
Decrease alertness, cognition, memory, learning, pyschomotor
Increase Impairment with or without sedation
What are the side effects of 1st Gen Antihistamines on Muscarinic?
Inhibit Muscarininc receptors
Decrease secretions -> dry mouth, dry eyes
Decrease smooth muscle contraction -> urninary retention
Increase Heart Rate -> Tachycardia
What are the side effects of 1st Gen Antihistamines on Serotonin receptors?
Increase appetite and weight gain
What are the side effects of 1st Gen Antihistamines on a- adrenergic?
Vasodilation - dizziness, postural hypotension
What are the side effects of 1st Gen Antihistamines on Cardiac ion Channels?
Increase QT interval
Increase Ventricular Arrhythmias
What are the 2 Contraindictions for 1st Generation Antihistamines?
Patients with Glaucoma and Postatic Hyperplasia
