#4 - Respiratory Flashcards
Bronchodilator
:
Salbutamol & Salmeterol
Salbutamol (T)(OS)(C)(SYR)(AI)(DPI)(RS) made from aspirin via fries rearrangement, Salmeterol (AI) = Selective beta2 adrenoceptor agonists. Effective in reversing bronchospasms of immediate phase
• B2 adrenoceptors (GPCR) are expressed by bronchial smooth muscle cells which are normally stimulated by adrenaline causing bronchial smooth muscle to relax so bronchioles will dilate. Administered during attack
• It activates a Gs protein (G stimulatory) which is a go between protein which diffuses across the internal surface of the cell membrane and activate the enzyme adenyl cyclase which coverts ATP Cyclic AMP
• This is a secondary messenger which diffuses off and activates the enzyme protein kinase A (PKA) which then phosphorylates myosin-light-chain kinase (MLCK). It normally regulates smooth muscle contraction but once it is phosphorylated it is inhibited. Therefore smooth muscle can no longer sustain a contraction = relaxation.
• B2 adrenoceptors also inhibit mediator release from mast cells and the release of (TNF-) from monocytes.
• Salbutamol (T)(OS)(C)(SYR)(AI)(DPI)(RS) made from aspirin via fries rearrangement, Salmeterol (AI)
• Indications = Salbutamol =Asthma and other conditions associated with reversible airways. Short acting
• Salmeterol = Reversible airways obstruction (asthma), COPD Long acting
Ipratropium (AI) Tiotropium (AI)(NS)
Muscarinic receptor antagonists = used to inhibit muscarinic receptors
• M3 receptors = most important and found on bronchial smooth muscle to facilitate bronchoconstriction, & glands to facilitate mucous secretion. Also in asthma irritant stimuli induce bronchoconstriction’s.
• Ipratropium is a muscarinic antagonist and will relax bronchial contractions caused by an increased vagal tone. It is given by inhalation & is not well absorbed into circulation = only affects muscarinic receptors
• It is non-discriminatory and may therefore bind and block M2 autoreceptors which are involved in negative feedback on Ach release and so increase Ach release = enhancing vagal mediated bronchoconstriction.
• Tiotropium by contrast is longer acting and functionally selective for M3 receptors. It actually binds to all but dissociates rapidly from M2 so avoiding a potential enhancing in vagal-mediated bronchoconstriction.
• Indications = Reversible airways obstruction particularly in COPD and rhinitis
Methylxanthines
= Phosphodiesterase inhibitor, non-selective adenosine receptor antagonist.
• 3 proposed mechanisms for therapeutic effects:
• 1) Inhibition of the intracellular enzyme phosphodiesterase (PDE) to raise intracellular levels of cAMP, as PDE inactivates it by converting it to 5’AMP. This makes more cAMP = bronchodilation
• 2) Competitive antagonism at adenosine A1 & A2 receptors. Adenosine acts as a bronchoconstrictor and releases histamine from lung mast cells. 3) Activation of histone deacetylase which inhibits the acetylation of core histones required for the transcription of inflammatory genes.
• Theophylline is a bronchodilator and given orally as not feasible to be given by inhalation
• It can be formulated as aminophylline which is often the methylxanthine prescribed
• Theophyllin (MRT)(C) Aminophylline (MRT)(INJ)
• Indications = Reversible airways obstruction, severe acute asthma
Corticosteroids
= anti-inflammatory in asthma
• Steroids which increase the airway calibre in asthma by reducing bronchial inflammatory reactions such as oedema formation, infiltration of immune cells, mucus hyper secretion & modifying allergic reactions
• Glucocorticoids inhibit/prevent the inflammatory components of both phase compared to bronchodilators which only reverse the bronchospasm of the immediate phase.
• Are lipid soluble so cross plasma membrane binding to intracellular receptors which migrate to the nucleus and interact with DNA to modify gene transcription and protein synthesis = inducing and inhibiting proteins
• 1) Enchance expression of annexin-1 2) Decrease the formation of Th2 cytokine which recruit eosinophils promote clonal expansion of B cells which switch to plasma cells to produce IgE an abnormal response.
• 3) Reduce the synthesis of cytokines which regulate mast cell production – long term steroid represses it
• Beclomethasone(DPI)(AI) Prednisolone (T)(INJ)(ST) Fluticasone (DPI)(AI)
Leukotriene receptor antagonists
- LTD4 and LTC4 are implicated as major mediators of bronchoconstriction and are produced from arachidonic acid via the enzyme 5-lipoxygenase
- Montelucast and Zafirlukast simply stop leukotrients from binding to their receptors (CysLT1)
- Their bronhodilatory effects are less than salbutamol and are generally used as 3rd lines drug as an add on therapy to inhaled corticosteroids and B2 agonists.
- Montelukast (T)(CT)(GRAN) Zafirlukast (T)
- Indications = Prophylaxis of asthma
Antihistamines
histamine H1 antagonist #No = generation
• Antihistamines are competitive inverse agonists that reduce the basal level of activity at histamine H1 receptors as well as blocking the agonist effect of histamine.
• #1st gen are lipophilic and cross the BBB = cause drowsiness and psychomotor impairment & also have some antimuscarinic side effects
• #2nd gen are non-sedating and are either more hydrophilic or more ionised at physiological pH. Don’t cross BBB well and have little sedative effect.
• #3rd gen are active metabolites/ optical isomers of second gen drugs =Desloratadine is an active metabolite of lortatadine and is a highly selective of peripheral h1 receptor antagonist and more potent
• #2Cetirizine (T)(OS) #2Loratadine (T)(INJ)(ST) #1Chlorphenamine (T)(OS)(SYR) #3Desloratadine (T)(OS)
• Indications = Symptomatic relief of allergy such as hay fever, chronic idiopathic urticaria
Azelastine
is an antihistamine used as a topical nasal spray and for more severe cases, a topical intranasal corticosteroid spray can be used (eg. beclomethasone/ Beconase®).
• There are topical nasal decongestants which contain ephedrine.
• These are a1-adrenoceptor agonists which produce local vasoconstriction and cause opening of the nasal passages. However, prolonged usage will impair ciliary activity in the nasal mucosa and usage is therefore restricted to no longer than 7 days.
Oxygen
increases alveolar oxygen tension in hypoxaemic patients = available as gas in oxygen cylinders
