Murdoch - Asthma Pharmacology Flashcards
Bronchial muscle tone is affected by parasympathetic, sympathetic and non-adrenergic non-cholinergic (NANC) influences. Bronchial muscle constriction tone is primarily driven by the [parasympathetic] system.
Sympathetic neurotransmitters act on [beta2 adrenoceptors] to [relax] smooth muscle. There is direct innervation by the vagus nerve, and the major receptors it acts upon to make bronchi [constrict] are [M3 receptors]. Sympathetic control directly innervates [blood vessels] but indirectly affects [airways] via the blood (after secretion from the adrenal medulla). Therefore, [sympathetic] bronchodilation of airways by beta2 agonists is by receptors in the muscle wall which are not directly innervated. Parasympathetic activity, in addition to causing bronchial muscles to [constrict], also causes mucus secretion. In addition to this innervation, there is also non-adrenergic non-cholinergic (NANC) innervation, mediated by nitric oxide (and vasoactive intestinal peptide) and this causes bronchial muscles to [relax]. Neuroinflammatory mediators (from sensory nerves) such as substance P and neurokinin A can also cause bronchial muscles to [constrict]. Sympathomimetic agents will cause bronchial muscle to [relax], and anticholinergics, acting via [M3 receptors] will cause bronchi to [relax].
Salbutamol (albuterol) is a short-acting bronchodilator. It is typically inhaled and acts quickly. As such it is used ‘as needed’ for symptomatic relief. It has no effect on the inflammatory aspects of asthma. What receptors does salbutamol act upon?
- a. alpha-1
- b. alpha-2
- c. beta-1
- d. beta-2
- e. beta-3
= d. beta-2
Salbutamol (albuterol) is a short-acting beta-agonist or SABA, which selectively acts on beta-2 adrenoceptors. Onset in minutes and duration a few hours. It is 29 times more selective for beta-2 over beta-1 receptors. With systemic distribution of the drug, cardiac side effects (tachycardia, dysrhythmia) may sometimes arise from its beta 1 activity, (along with the effects of beta-2 mediated vasodilation, and potential hypokalaemia due to beta-2 stimulation of Na+/K+ ATPase (increases muscle uptake of potassium)). Muscle tremor may also be seen as a beta-2 effect. There are numerous other potential side effects, such as headache, and beta-2 mediated glycogenolysis causing hyperglycaemia.
Caffeine appears to cause some mild bronchodilation for a few hours (and so should be avoided before spirometry testing). Theophylline is a related drug (a methylxanthine) and was once used as a bronchodilator, but its narrow therapeutic window and signiicant side effects mean it is not favoured. What is the mechanism of bronchodilation for methylxanthines?
- a. beta-2 agonist
- b. beta-2 antagonist
- c. Phosphodiesterase inhibitor
- d. Stimulation of myosin ATPase, directly
- e. Sympathetic agonist
= c. Phosphodiesterase inhibitor.
Caffeine and theophylline, as methylxanthines, inihibit phosphodiesterase, and so raise cAMP levels (see diagram below) and cause smooth muscle relaxation. There may be other mechanisms such as blocking adenosine receptors (which affect adenyl cyclase - see diagram below). Side effects are well-known in coffee drinkers, and include diuresis, insomnia, and nervousness. Theophylline may also cause dysrhythmia, GI disturbances and seizures.
Ipratropium bromide is an inhaled receptor antagonist used for its short term bronchodilation and inhibition of mucus secretion. It has relatively few side-effects. What type of receptor does it antagonise?
- a. M1
- b. M2
- c. M3
- d. M4
- e. Non-selective M1-M5 inclusive
= e. Non-selective M1-M5 inclusive
Ipratropium is a non-selective muscarinic antagonist, causing bronchodilation and reduced mucus secretion. Because it is highly polar it is not well absorbed into the circulation and so its systemic side effects are limited when used topically in the airways, despite it being non-selective in its muscarinic antagonism. It has no effect on the inflammatory aspects of asthma.
What are the 5 types of Muscarinic receptors and their effects?
Muscarinic receptor types (normal actions, not the effect of antagonists).
- M1 - Neural (autonomic ganglia and cerebral cortex) CNS excitation (improved cognition?) and gastric secretion
- M2 - Cardiac (heart and CNS), cardiac and neural inhibition
- M3 - Exocrine glands and smooth muscle (salivary and GI secretions and smooth mm contraction, ocular accommodation, and vasodilation due to release of nitric oxide from adjacent endothelia)
- M4 and M5 - CNS. Not much is known about these subtypes.
Various classes of drug act as sympathomimetics in asthma treatment.
Label A, B, C, D.
Options: Antimuscarinics, Methylxanthines, beta-agonists, beta antagonists
The correct answer is:
A → Antimuscarinics,
B → Methylxanthines,
C → Methylxanthines,
D → beta-agonists
Glucocorticoids are synthesised from cholesterol in the zona fasciculata of the adrenal cortex, under the influence of ACTH from the anterior pituitary. They have broad ranging effects including decreased glucose uptake and utilisation, and increased gluconeogenesis (tending to raise blood glucose). They also cause decreased protein synthesis and increased protein catabolism (causing muscle wasting), and are permissive for lipase activation. They may have some mineralocorticoid action (depending on the type), especially in non-physiological concentrations. In asthma, glucocorticoids are used for their broad anti-inflammatory effects (they do not have action as bronchodilators);
- Reduced neutrophil egress, and reduced activation of neutrophils, macrophages and mast cells
- Decreased Th cell activation, reduced clonal proliferation of T-cells and switch from Th1 to Th2 type responses
- Suppression of arachidonic acid release (inhibition of phospholipase A2), and reduced cyclo-oxygenase II expression (reduces prostanoid production)
- Reduced generation of many cytokines (IL-1,2,3,4,5,6,8, TNF-alpha)
- Reduced complement concentration
- Reduced inducible nitric oxid formation
- Reduced histamine release from basophils and mast cells
- Increased IL-10 and other anti-inflammatory factors
= c. Cytoplasmic and nuclear receptors
The diverse effects of glucocorticoids are mediated by binding to intracellular receptors which, after dimerisation, migrate to the nucleus and modify gene expression (both up and down regulation). There are also effects from cytosolic receptors, and some membrane bound receptors (with tissue-specific variants). It is said that almost 1% of genome expression can be affected by glucocorticoids. In asthma, the desirable effects are thought to be the result of;
- reduced clonal proliferation of Th cells (due to less IL-2), which means fewer eosinophils are recruited from Th2 cytokines. IL-5 inhibition reduces eosinophils. reduced IL-3 means fewer mast cells are produced
- reduced vasodilators PGE2 PGI2 due to COX-2 inhibition
Serious side effects from inhaled glucocorticoids are uncommon. Use of spacer devices with inhaled glucocorticoid therapy in asthma helps reduce which important unwanted effect?
= Oral candidiasis.
Oropharynygeal candidiasis is a yeast infection (Candida sp.). It can be seen with inhaled glucocorticoids due to the suppression of immune responses at a local level. Spacer devices reduce this by allowing the drug to be inhaled into deeper airways more completely, rather than being inhaled directly onto the oropharyngeal mucosa. Spacers also have other benefits in delivering the drug more effectively.
In other circumstances, Candida may also infect the skin and the vagina (where the condition is called ‘thrush’). Oropharyngeal candidiasis may be called oral thrush.
Leukotrienes act on receptors in respiratory mucosa and inflammatory cells. Leukotriene modifying agents may be taken in asthma (as long term modifiers), and seem to reduce bronchoconstriction and inflammation. Zileuton is a leukotriene pathway modifier. It inhibits production of leukotrienes from arachidonic acid. Which enzyme is inhibited to block leukotriene modification, in this pathway?
- a. Phospholipase A2
- b. 5-Lipoxygenase
- c. Cyclo-oxygenase
- d. TXA2 synthase
= b. 5-Lipoxygenase
Phospholipase A2 releases arachidonc acid from membrane phospholipids, and 5-lipoxygenase then generates leukotrienes. LTB4 is an important chemotaxin, and LTC4, D4 and E4 are bronchoconstrictors and increase vascular permeability. In addition to lipoxygenase inhibition, antagonism of leukotrienes can also be achieved by leukotriene receptor blockers (montelukast and zafirukast).
Drugs used in Asthma?
Omalizumab is a monoclonal antibody. It may be used in allergic rhinitis and asthma with confirmed significant allergic aetiology. What is the antibody directed against?
The correct answer is: IgE
- Omalizumab is an anti IgE antibody. By binding to serum IgE it prevents the effective binding of IgE to its receptor and activating mast cells (and basophils), and the resulting inflammatory cascade of preformed and newly-synthesised inflammatory mediators.
- Other antibody treatments are directed against interleukin-5. IL-5 is a potent eosinophil development and chemotactic factor. They may be used in eosinophilic asthma which has proven hard to treat.
- Mast cells: Other agents such as chromoglycate / cromolin may be used as ‘mast cell stabilisers’ to ‘prevent degranulation’ for prophylaxis against known allergens or exercise-induced asthma, but their use is uncommon now, and mechanism of action unclear.
Compare the drugs used in the Immediate phase and the Late phase of Asthma
