6B. Pharmacology of antihistamines, bronchodilators & corticosteroids Flashcards
Histamine
- Basic amine stored in mast cells & basophil granules
- H1, H2, H3, H4
- All G-protein coupled (H1 & H2 - increase cAMP)
H1 actions:
- Contracts smooth muscle of ileum, bronchi, bronchioles & uterus
- Dilates blood vessels & causes reddening of skin & itch
H1 pathophysiological role:
- Type I hypersensitivity e.g. allergic rhinitis & urticaria
Antihistamines
- Refers to H1-receptor antagonists (-ine)
- 1st gen (cross CNS), 2nd gen & 3rd gen (cardio safe)
- Most oral antihistamines are well absorbed & effective for 3-6 hours (except loratadine)
- Mainly metabolised in liver, excreted in kidneys
S/E: Antimuscarinic effect
- Blurred vision
- Dryness of mouth
- Constipation
- Urinary retention
Leukotriene receptor antagonist (LTRA)
Cysteinyl leukotrienes (LTC4, LTD4 & LTE4) act on CysLT1 & CysLT2 receptors expressed in respiratory mucosa & infiltrating inflammatory cells
Montelukast antagonise only CysLT1:
- Relief of season AR symptoms
- Prophylaxis & treatment of asthma
- Prevention of exercise-induced asthma
Montelukast
Decrease early & late responses to inhaled allergen
Reduce sputum eosinophilia, but no clear evidence that they modify the underlying inflammatory process in chronic asthma
In asthma less effective than salbutamol, but has additive effects when used together
Generally well tolerated, ADRs consisting mainly of headache & GI disturbances
Sodium cromoglycate
- Mechanism not fully understood - they are mast cell stabilisers & prevent histamine release from mast cell, but in asthma this is not the basis of its action
- Has no direct effect on smooth muscle
- Prophylactically, they reduce immediate- & late-phase asthmatic responses & reduce bronchial hyper-reactivity
- Weak anti-inflammatory effects
- Short duration of action
- Given by inhalation as aerosols or dry powders & topically (eye drops, intranasal) for allergic conjunctivitis/rhinitis
Corticosteroids (preventers)
- Intranasal steroids prevent & relieve nasal symptoms associated with early & late phase reactions
- Relieve nasal congestion, itching, rhinorrhoea & sneezing
- Some relief in a few days, but full response can take several weeks
MOA complex - unknown whether they penetrate the nasal mucosa or act on target cells
- Affect PGs, leukotrienes & mast cells
- Inhibit T lymphocytes, particularly TH2 cells, cytokine production or action & eosinophil recruitment
Inhaled/intranasal corticosteroids - ADRs
Intranasal:
- Dryness, burning, stinging, sneezing, contact dermatitis
- Epitaxis - 5-10%
- Septal perforations are rare - counsel on appropriate technique
Inhaled:
- Oropharyngeal candidiasis (thrush)
- Sore throat & croaky/hoarse voice
- Use of spacers decrease oropharyngeal deposition of the drug & reduce AEs
Regular, high dose, can produce some adrenal suppression, especially in children
- Less likely with fluticasone & mometasone as these drugs are poorly absorbed from the GI tract & undergo almost complete presystemic metabolism
Small but significant reduction in growth velocity in a 12-month study of children (6-9 years) treated with beclomethasone 336 mcg/d
Asthma/COPD - Bronchial physiology
Parasympathetic innervation:
- Predominates in bronchial smooth muscle
- M3 pharmacologically most important in airway disease - found on bronchial smooth muscles & gland cells - medicates bronchoconstriction & mucuos secretion
Sympathetic innervation:
- Sympathetic nerves innervate tracheobronchial blood vessel & glands but not smooth muscle
- Beta2 abundant on bronchial smooth muscle, mast cells, epithelium, glands, alveoli
- Beta agonists relax bronchi, inhibits release from mast cells & increase mucociliary clearance
Bonchodilators: Beta2 agonists vs muscarinic antagonists
Beta2 agonists:
- Stimulation of Beta2 causes activation of a G-protein with increase in cAMP causing inactivation of myosin light chain kinase
+ Also enhances Ca2+ concentration leading to relaxation of smooth muscle
Muscarinic antagonists:
- Block binding of Act to M3 receptors thereby inhibiting smooth muscle cell contraction
Bronchodilators
Reverse bronchospasm immediate phase:
- SABAs: Salbutamol, terbutaline
- LABAs: Salmeterol, formoterol, indacaterol, olodater, vilanterol
- SAMAs: Ipratropium bromide
- LAMAs: Tiotropium, glycopyrronium, umeclidinium
- Leukotriene receptor antagonists
- Theophylline
Adverse effects - Beta2 agonists & muscarinic antagonists
Beta2-adrenoreceptor agonists:
- Most common: Tremor, tachycardia & cardiac dysrhythmia
Muscarinic antagonists:
- Epitaxis, nasal dryness, irritation (if sprayed for rhinitis, rhinorrhoea)
- Anticholinergic side effects e.g. dry mouth, urinary retention, palpitations, GI motility disturbances (constipation)
- Caution in glaucoma
Theophylline: MoA, ADRs, C/I
- MoA: Inhibition of phosphodiesterase (PDE) with increase in cAMP &/or cGMP with resultant bronchodilation
- Narrow therapeutic index
- ADRs include serious CV (dysrhythmia) & CNS (seizures) effects
C/I: Coronary artery disease & caution in cardiac disease - Check for interactions especially with drugs inhibiting CYP enzymes e.g. erythromycin, clarithromycin, ciprofloxacin, diltiazem , fluconazole
- IV formulation - aminophylline (increased solubility)
Corticosteroids in asthma
- Inhibit & prevent inflammatory component of early & late phase, & prevent progression of chronic asthma
- Inducing gene transcription for IL-2 & restrain proliferation of Th cells, decreasing formation of Th2 cytokines that recruit & activate eosinophils
- Promote production of IgE & expression of IgE receptors & inhibit PGE2 & PGI2
- Inhibit the influx of eosinophils into the lung, upregulate β2-adrenoceptors, decrease microvascular release from eosinophils by inhibiting the production of cytokines (e.g. IL-5 & granulocyte-macrophage colony-stimulating factor) that activate eosinophils
- Reduce synthesis of IL-3 (regulates mast cell production), which may be why long-term use reduces the mast cell numbers in the respiratory mucosa & suppresses the early-phase response to allergens & exercise
Anti IgE treatments (mabs)
Omalizumab: Humanised monoclonal anti-IgE antibody
- Allergic asthma & AR
- Severe persistent disease who have required continuous / frequent treatment with OC
- Expensive
Mepolizumab:
- Inhibition of IL-5
- IL-5 key cytokine involved in growth, differentiation & activation of eosinophils
