pharmacology Flashcards
where are preganglionic and postganglionic neurones found?
preganglionic neurones = found in brainstem
postganglionic neurones = found in walls of bronchi and bronchioles
what are the two types of postganglionic neurones?
cholinergic and noncholinergic
what does stimulation of cholinergic fibres cause in parasympathetic division?
- bronchial smooth muscles contract mediated by M3 muscarinic ACh receptors on airway smooth muscle cells.
- increased mucus secretion mediated by M3 muscarinic ACh receptors on gland (goblet) cells.
what does stimulation of postganglionic noncholinergic fibres cause in the parasympathetic division?
bronchial smooth muscle relaxation mediated by nitric oxide and vasoactive intestinal peptide (VIP)
what does stimulation of postganglionic fibres cause in sympathetic division?
-B2 adrenoreceptors on airway smooth muscle are activated by adrenaline causing bronchial smooth muscle relaxation.
-there is decreased mucus secretion
-increased mucociliary clearance
-vascular smooth muscle contraction
( all stages activated by B2 adrenoreceptors)
Describe the process of contraction in smooth muscle due to calcium.
Transmitter or hormone (parasympathetic) activates GPCR >which activates Gq11 and therefore phospholipase C > IP3 makes its way to IP3 receptor/calcium channel – allowing calcium to leave and enter the cytoplasm > cell depolarises >more calcium is able to enter via voltage gated calcium channels > causes contraction.
How is contraction initiated by ca2+ in smooth muscle?
ca2+ > ca2+ calmodium > activates MLCK (myosin light chain kinase) > phosphorylates myosin cross bridges which bind to actin > generation of contraction
how does relaxation of smooth muscle occur?
adrenaline binds to beta receptors> activates G5 > activates AC > converts ATP to cAMP > activates PKA > either phosphorylates and inhibits MLCK or phosphorylates and stimulates myosin phosphatase > relaxation of bronchial smooth muscle
- PDE determines duration of response.
describe the relationship between myosin phosphatase and MLCK.
dephosphorylation of MLCK causes myosin phosphatase to change to MLCK(myosin light chain kinase) and phosphorylation returns it to myosin phosphatase.
what are the pathological changes to bronchioles that result from long standing inflammation in asthma?
- increased mass of smooth muscle
- accumulation of interstitial fluid (oedema)
- increased secretion of mucus
- epithelial damage
- sub-epithelial fibrosis
- epithelial damage, exposing sensory nerve endings contributes to increased sensitivity of airways to bronchochonstriction.
what are the different types of hypersensitivity in asthma?
type 1 hypersensitivity = early phase, bronchospasm and acute inflammation
- type 4 hypersensitivity = late phase, bronchospasm and delayed inflammation
How do nonatopic individuals respond to an allergen?
- phagocytosis by dendritic cells > low level Th1 cells mediated immune response involving IgG and macrophages
how do atopic individual respond to an allergen?
phagocytosis by dendritic cells> strong Th2 response, antibiody mediated immune response involving IgE
How does allergic asthmas develop?
the allergen is processed by and antigen presenting cell > present to T CD4+ cells > differentiate into Th0 then Th1 and Th2 cells > Th2 cells activate B cells by binding to them and IL-4 production > B cells mature into IgE secreting P cells
- eosinophils are also produced in response to IL-5 released from Th2 cells and mast cells express IgE receptors in response to IL-4 and IL-13.
= stimulation of calcium entry into mast cells and release from intracellular stores > releases secretory granules containing histamine and other substances to cause smooth muscle contraction > release of substances causing inflammation.
what drugs are used as relievers in asthma?
(act as bronchodialators)
- short acting B2 adrenoreceptor agonists (SABAs)
- long acting B2 adrenoreceptor agonists (LABAs)
- cycLT1 receptor antagonists
- methyxanthines
what drugs are used as controllers/ preventers in the treatment of asthma?
- glucocorticoids
-cromoglicate
-humanised monoclonal IgE antibodies
(all act as anti-inflammatory agents that reduce airway inflammation)
-methyxanthines
describe the aerosol use of drugs for asthma.
- slow absorption from lung surface and rapid systemic clearance
- low dose delivered rapidly to target
- low systemic concentration
- low adverse affects
- distribution reduced in severe airway disease
- compliance good with bronchodialators, less with anti-inflammatory drugs
- difficult for some people to use
- effective in mild to moderate disease
Describe oral use of drugs in treatment of asthma.
- good oral absorption and slow systemic clearance
- high systemic dose necessary to achieve appropriate lung conc.
- high systemic conc.
- high incidence of adverse effects
- distribution unaffected by airway disease
- good compliance
- effective in severe disease
what are bronchodialators?
- B2 adrenoreceptor agonsits
- act as physiological antagonists of all spasmogens.
what are SABAs?
- short acting agonists
- salbutamol aka albuterol, terbutaline
- first line for mild intermittent asthma
- relievers taken as needed
- act rapidly via inhalation
- increase mucus clearance and decrease mediator release from mast cells and monocytes
- have few adverse affects (fine tremor, tachycardia, cardiac dysrhythmia, hypokalaemia)
what are LABAs?
- long acting B2 adrenoreceptors
- NOT recommended for acute elief of bronchospasm
- useful for nocturnal asthma
- should not be used as monotherapy, can be used as an add on
- MUST BE CO-ADMINISTERED WITH A GLUCOCORTICOID
- should be selective
what do cysteinyl leukotriene (CystLT1) receptor antagonists do?
- act competitively at the CysLT1 receptor.
- stops CysLTs infiltrating inflammatory cells causing smooth muscle contraction, mucus secretion and oedema.
- e.g motelukast, zafirlukast
- effective as add on therapy against early and late bronchospasm in mild persistent asthma.
- effective against antigen-induced and exercise induced bronchospasm
- oral
- not recommended for severe asthma
- can cause headaches and GI upset
what are methyxanthines?
- theophylline and aminophylline
- combine bronchiodilator and anti-inflammatory actions, inhibit mediator release from mast cells, increase mucus clearance
- increase diaphragmatic contractability and reduce fatigue - may improve ventilation
- second line, used in combination with B2 adrenoreceptor agonsits and glucocorticoids
- oral
- very narrow therapeutic window
- side effects; dysrhythmia, seizures, hypotension, nausea, vomiting, abdominal discomfort, headaches
what does cortisol do?
- decrease (D)inflammatory response
- D immunological response
- increase (I) gluconeogenesis
- I glucose output from liver
- D glucose utilization
- I protein catabolism
- I bone catabolism
- I gastric acid and pepsin secretion
