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Respiratory > pharmacology > Flashcards

pharmacology Flashcards

1
Q

where are preganglionic and postganglionic neurones found?

A

preganglionic neurones = found in brainstem

postganglionic neurones = found in walls of bronchi and bronchioles

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2
Q

what are the two types of postganglionic neurones?

A

cholinergic and noncholinergic

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3
Q

what does stimulation of cholinergic fibres cause in parasympathetic division?

A
  • 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.
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4
Q

what does stimulation of postganglionic noncholinergic fibres cause in the parasympathetic division?

A

bronchial smooth muscle relaxation mediated by nitric oxide and vasoactive intestinal peptide (VIP)

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5
Q

what does stimulation of postganglionic fibres cause in sympathetic division?

A

-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)

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6
Q

Describe the process of contraction in smooth muscle due to calcium.

A

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.

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7
Q

How is contraction initiated by ca2+ in smooth muscle?

A

ca2+ > ca2+ calmodium > activates MLCK (myosin light chain kinase) > phosphorylates myosin cross bridges which bind to actin > generation of contraction

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8
Q

how does relaxation of smooth muscle occur?

A

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.

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9
Q

describe the relationship between myosin phosphatase and MLCK.

A

dephosphorylation of MLCK causes myosin phosphatase to change to MLCK(myosin light chain kinase) and phosphorylation returns it to myosin phosphatase.

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10
Q

what are the pathological changes to bronchioles that result from long standing inflammation in asthma?

A
  • 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.
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11
Q

what are the different types of hypersensitivity in asthma?

A

type 1 hypersensitivity = early phase, bronchospasm and acute inflammation
- type 4 hypersensitivity = late phase, bronchospasm and delayed inflammation

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12
Q

How do nonatopic individuals respond to an allergen?

A
  • phagocytosis by dendritic cells > low level Th1 cells mediated immune response involving IgG and macrophages
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13
Q

how do atopic individual respond to an allergen?

A

phagocytosis by dendritic cells> strong Th2 response, antibiody mediated immune response involving IgE

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14
Q

How does allergic asthmas develop?

A

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.

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15
Q

what drugs are used as relievers in asthma?

A

(act as bronchodialators)

  • short acting B2 adrenoreceptor agonists (SABAs)
  • long acting B2 adrenoreceptor agonists (LABAs)
  • cycLT1 receptor antagonists
  • methyxanthines
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16
Q

what drugs are used as controllers/ preventers in the treatment of asthma?

A
  • glucocorticoids
    -cromoglicate
    -humanised monoclonal IgE antibodies
    (all act as anti-inflammatory agents that reduce airway inflammation)
    -methyxanthines
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17
Q

describe the aerosol use of drugs for asthma.

A
  • 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
18
Q

Describe oral use of drugs in treatment of asthma.

A
  • 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
19
Q

what are bronchodialators?

A
  • B2 adrenoreceptor agonsits

- act as physiological antagonists of all spasmogens.

20
Q

what are SABAs?

A
  • 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)
21
Q

what are LABAs?

A
  • 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
22
Q

what do cysteinyl leukotriene (CystLT1) receptor antagonists do?

A
  • 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
23
Q

what are methyxanthines?

A
  • 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
24
Q

what does cortisol do?

A
  • 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
25
Q

what are mineralocorticoids?

A
  • regulates the retention of salt and water by the kidney

- unwanted in the treatment of inflammatory conditions

26
Q

which forms of cortisol are frequently used to treat asthma?

A
  • synthetic derivatives of cortisol with little or no mineralocorticoid
  • beclometasone, budesonide
27
Q

how should glucocorticoids be administered?

A

-inhalation to minimise adverse effects of mainstay treatment

28
Q

Describe the action of glucocorticoids.

A
  • signal via nuclear receptors
  • are lipophilic molecules that enter by diffusion across the plasma membrane
  • within the cytoplasm they combine with GRalpha producing dissociation of inhibitory heat shock proteins. the activated receptor translocates to the nucleus aided by importins
  • within the nucleus activated receptor monomers assemble into homodimers and bind to glucocorticoid response elements in the promoter regions of specific genes
  • transcription of specific genes is either switched on or switched off to alter mRNA levels and the rate of synthesis or mediator proteins.
29
Q

what are glucocorticoids effects on gene transcription?

A
  • increase transcription of genes encoding anti-inflammatory proteins and decrease transcription of genes encoding inflammatory proteins
  • they recruit deacetylases to activated genes and switch off gene transcription
  • decrease formation of Th2 cytokines and cause apoptosis
  • reduce number of mast cells and decrease FCE expression
  • prevent IgE production
30
Q

when are glucocorticoids effective?

A
  • long term use in combination with a LABA
    -in mild/moderate asthma inhaler use
    (beclometasone, budesonide or fluticasone
  • side effects = dysphonia, oropharyngeal candidiasis
    -prednisolone used in severe or rapidly deteriorating asthma.
31
Q

Describe cromones.

A
  • second line drugs now infrequently used prophylactically (prevention)
  • weak anti inflammatory effect
  • sodium cromoglicate, delivered by inhalation, more effective in children and young adults.
32
Q

what does omalizumab do?

A
  • a monoclonal antibody directed against IgE which prevents attachment to FCE receptors, suppressing mast cell response
  • requires IV injection
33
Q

what is mepolizumab?

A
  • monoclonal antibodies directed at IL-5
  • for asthma with severe eosinophilia
  • very expensive
34
Q

how is COPD characterised ?

A
  • by increased resistance to airflow during expiration
35
Q

describe muscarinic acetylcholine receptors role in the airways

A
  • reducing parasympathetic neuroeffector transmission with muscarinic receptor antagonists is important in the treatment of COPD
  • muscarinic receptor antagonists stop bronchoconstriction caused by smooth muscle M3 receptor activation in response yo ACh released from postganglionic parasympathetic fibres.
36
Q

what are the three muscarinic acetylcholine receptors in the airways

A

M1 - found in the ganglia - facilitates fast neurotransmission mediated by ACh acting on nicotinic receptors.

  • M2 - found in postganglionic neurone terminals - acts as inhibitory autoreceptors reducing the release of ACh
  • M3 - found in ASM cells - mediate contraction to ACh (also present in mucus secreting cells)
37
Q

what muscarinic receptor antagonists are used in the treatment of COPD.

A 
SAMA = ipratropium 
LAMAs = tiotropium, glycopyrronium, aclidinium, umeclidinium
38
Q

what do the muscarinic receptor antagonists used in COPD do?

A
  • all are administered by inhalation. Quaternary ammonium group reduces absorption and systemic exposure avoiding multiple potential adverse effects .
  • have delayed bronchodilator action relative to a SAMA
  • reduce bronchospasm caused by irritant stimuli and also block ACh mediated basal tone
  • decrease mucus secretion
  • effect mainly palliative, no effect on progression of COPD
  • few adverse effects
  • ipratropium is a non-selectibe blocker of M1, M2 and M3 receptors, preferred agents with some selectivity are available.
39
Q

why are selective M3 blockers superior to ipratropium?

A
  • (tiotropium, glycopryrronium, aclidinium, umeclidinium)

- block of M3 (and M1) is desirable but but of M2 is not because it does an opposite job to the others.

40
Q

when are LABA/LAMA combinations most effective?

A
  • when both drugs are deposited in the same location in the airways.
41
Q

what treatments can be given in COPD appart from SABA/LAMA/LABAs

A
  • rofumilast is an inhibitor of phosphodiesterase-4 (PDE4) expressed in neutrophils, T cells and macrophages. (reduced inflammation)
  • glucocorticoids can be administered with LAMA/LABAs
  • triple inhalers

Respiratory (17 decks)

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