Antihistamines

Question 1

What are the 2 First Generation Antihistamines

Answer 1

Chlorpheniramine, Diphenhydramine

Question 2

What are the 2 Second Generation Antihistamines

Answer 2

Cetirizine, Fexofenadine

Question 3

How is Histamine synthesised?

Answer 3

Histidine decarboxylase catalyses the conversion of Histidine to Histamine, with the release of CO2

Question 4

What are the Histamine Metabolisers?

Answer 4

1) Histamine N-methyltransferase
2) Diamine oxidase
3) Monoamine Oxidase

Question 5

What are the ceullular sources of histamine?

Answer 5

1) Mast Cells
2) Basophils
3) ECL Cells
4) Histaminergic neurons

Question 6

How are Anti-Histamines Released?

Answer 6

Mast Cell Degranulation: IgE Mediated Allergy
1) Mast cells with IgE bound on surface
2) Allergen binding cross links IgE
3) Mediators released

Question 7

What are the Biological actions of Histamine?

Answer 7

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

Question 8

What are the effects of Histamine on Smooth Muscle?

Answer 8

Contraction of smooth muscles (Bronchial, Intestinal)

Question 9

What are the effects of Histamine on Blood Vessels?

Answer 9

Vasodilation - Endothelium produced Nitric Oxide
Increased Vascular Permeability - contraction of endothelial barrier and increase gap junction

Question 10

What are the effects of Histamine on skin?

Answer 10

Immediate Wheal (swelling - vascular permeabilty) and Flare (redness - Vasodilation) reaction

Question 11

What are the effects of Histamine on mast cells and basophils?

Answer 11

Increased release of histamine and other mediators

Question 12

What are the effects of Histamine on neurons?

Answer 12

Modulates histaminergic neurotransmissions, affecting sleep/wake cycle, arousal, alertness, attention, cognition, learning and memory

Question 13

What are the effects of Histamine on Immune system?

Answer 13

Immunomodulation

Question 14

What type of Receptor are Histamine Receptors?

Answer 14

GPCR

Question 15

What are H1 receptors and what is the Signalling Pathway?

Answer 15

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

Question 16

What are H1-Antihistamines?

Answer 16

Inverse Agonist

Question 17

What is the mechanism of action of H1-Antihistamines?

Answer 17

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

Question 18

What are the clinical uses for Antihistamines?

Answer 18

1st Gen - Non-Allergic conditions
2ns Gen - Mild-moderate allergy

Question 19

What are the clinical uses of 1 Generation Antihistamines?

Answer 19

Sedating - Non Allergic Conditions (used for its adverse drug reactions)
Motion sickness/vertigo, nauseu/vomiting, insomnia and peri operations (DIPHENHYDRAMINE)

Question 20

What are the clinical uses of 2nd Generation Antihistamines?

Answer 20

Non-Sedating - Mild moderate allergies
Allergic rhinitis, Allergic Conjunctivitis, Allergic Urticaria (hives), Food Allergy, Mastocytosis

Question 21

What are the conditions treated with H1-Antihistamines that have strong evidence base?

Answer 21

Second generation: Allergic Rhinitis, Allergic Cojunctivitis, Allergic Urticaria

Question 22

What are the conditions treated with H1-Antihistamines that have weak evidence base?

Answer 22

URTI, Sinusitis, non-specific cough

Question 23

What are the conditions treated with FIRST GENERATION H1 antihistamine that have weak evidence base?

Answer 23

Insomnia, Perioperative Sedation, Motion Sickness, vertigo

Question 24

What is mechanism of Antihistamines?

Answer 24

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

Question 25

What is the effect of Antihistamines on H1 Receptor?

Answer 25

Blockage, resultign in decrease vasodilation, vascular permeability, wheal and flare and itch

Question 26

What is the effect of Antihistamines on Gaq?

Answer 26

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

Question 27

Differences between 1st and 2nd Generation

Answer 27

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

Question 28

What are the receptors in which side effect form 1st generation antihistamines derive from?

Answer 28

CNS H1 receptor, Muscarinic, Serotonin receptors, a-adrenergic receptors, Cardiac ion channels

Question 29

What are the side effects of 1st Gen Antihistamines on CNS H1?

Answer 29

Decrease alertness, cognition, memory, learning, pyschomotor Increase Impairment with or without sedation

Question 30

What are the side effects of 1st Gen Antihistamines on Muscarinic?

Answer 30

Inhibit Muscarininc receptors Decrease secretions -> dry mouth, dry eyes Decrease smooth muscle contraction -> urninary retention Increase Heart Rate -> Tachycardia

Question 31

What are the side effects of 1st Gen Antihistamines on Serotonin receptors?

Answer 31

Increase appetite and weight gain

Question 32

What are the side effects of 1st Gen Antihistamines on a- adrenergic?

Answer 32

Vasodilation - dizziness, postural hypotension

Question 33

What are the side effects of 1st Gen Antihistamines on Cardiac ion Channels?

Answer 33

Increase QT interval Increase Ventricular Arrhythmias

Question 34

What are the 2 Contraindictions for 1st Generation Antihistamines?

Answer 34

Patients with Glaucoma and Postatic Hyperplasia