antihistamines

Question 1

targets for antihistamines

Answer 1

• G-protein coupled receptor
• HR1: immediate allergic response (mast cell degranulation, release histamines)

Question 2

chemical classes of antihistamines

Answer 2

1) alkylamines
- 1st gen: chlorpheniramine, brompheniramine
- 2nd gen: acrivastine

2) piperazine
- 1st gen: hydroxyzine
- 2nd gen: cetirizine, levocetirizine

3) piperidine
- 1st gen: ketotifen
- 2nd gen: loratadine, desloratadine, fexofenadine

4) ethanolamines
- 1st gen: diphenhydramine
- no 2nd gen

5) phenothiazines
- 1st gen: promethazine
- no 2nd gen

6) others
- no 1st gen
- 2nd gen: azelastine, olopatadine

Question 3

histamines - general

Answer 3

• plasma t/12 = 5-10 mins
• major metabolising enzymes:
  1) histamine N-methyltransferase
  2) diamine oxidase (DAO)
  3) monoamine oxidase (MAO)

Question 4

sources of histamines

Answer 4

1) mast cells: activated after IgE cross link
2) basophils
3) enterchromaffin-like (ECL) cells: related to stomach
4) histaminergic cells

Question 5

mast cell degranulation

Answer 5

. IgE mediated allergy
- process:
1) mast cell with bound IgE recognise allergen
2) cross linking
3) release histamine
4) mast cell degranulation
5) regeneration
- products released during degranulation
1) histamine
2) beta hexosaminidase (marker for experiments)
3) heparin (anticoagulation factor)

. non IgE mediated pseudoallergy
- types of non IgE mediators:
1) IgG
2) drugs: opioids, vancomycin (antibiotics), radiocontrast medium
3) anaphylatoxin: C5a, C3a
4) substance P
5) bacterial products: lipopolysaccharides (LPS)
6) kit ligand: stem cell factor

Question 6

physiological reactions of histamine

Answer 6

1) smooth muscle contraction (bronchial)

2) vasodilation (endothelial derived NO)
- histamine bind to endothelial histamine -> release NO -> relax vascular smooth muscle

3) increase vascular permeability
- contraction of endothelial barrier + vasodilation
- increase gap junction
- contents leak out -> extravasation & oedema

4) sensory nerve to mediate pain and itch

5) immediate symptoms of wheal-and-flare reaction (redness & swelling) on skin

6) stimulate gastric acid secretion (proton pump)

7) increase release of histamine & other mediators by mast cells and basophils
- positive feedback loop

8) modulation of histaminergic neurotransmission, sleep/wake cycle, arousal, attention, alertness, cognitive, learning, memory
- antihistamine block these = drowsiness

9) immunomodulation
- immunosuppressants block T cells

Question 7

process of H1 receptor activation

Answer 7

1) H1 receptor + P alpha q -> activate phospholipase C beta
2) PLCbeta + PIP2
- DAG -> protein kinase C
- InsP3 -> Ca2+
3) PLCbeta stimulates
- NO synthase (NOS) to produce NO
- phospholipase A2 (PLA2) to produce arachidonic acid

Question 8

antihistamines - general

Answer 8

• inverse agonist
• stabilise H1 receptor in inactive form

Question 9

1st gen vs 2nd gen antihistamine

Answer 9

1) sedating
- 1st: yes, 2nd: no

2) H1 receptor affinity
- 1st: low, can bind to others
- 2nd: high

3) other effects cuz bind to other receptors
- 1st: anti-muscarinic cholinergic, anti-adrenergic, anti-hydroxytryptaminergic (5-H5)
- 2nd: nil

4) lipophilicity
- 1st: high, 2nd: low

5) MW
- 1st: smaller, 2nd: larger

6) BBB
- 1st: pass readily, 2nd: less readily

7) p-glycoprotein efflux pump
- 1st: no interaction, stay inside longer
- 2nd: high affinity, no accumulation

8) CNS H1 receptor affinity
- 1st: high
- 2nd: low, 0 for fexofenadine, 30% for cetirizine

9) onset of action
- 1st: 2-3 hrs, 2nd: 1-2 hrs

10) duration of action
- 1st: about 12 hrs, 2nd: 24 hrs, once daily

Question 10

side effect of 1st gen antihistamines

Answer 10

1) CNS
- lower alertness, cognitive, learning, memory, psychomotor skills

2) muscarinic
- increase dry mouth/eyes, urinary retention, sinus tachycardia, blurred vision, constipation

3) serotonin receptors
- increased appetite & weight loss (ketotifen)

4) alpha adrenergic receptors
- dizziness, postural hypotension (promethazine)

5) calcium ion channels
- increase QT interval, ventricular arrhythmia

. not for patients with occupations that work with heavy machinery, recommend fexofenadine instead
. CI: glaucoma (esp narrow angle), prostatic hyperplasia
. drug abuse: euphoria, hallucination (hydroxyzine, diphenhydramine)