asthma Flashcards
(24 cards)
Asthma is an — disease of the –
It is characterized by – airflow —-, and —
Usually caused by inhaling an — (e.g. pollen, mold,dust)
5-10% of population
Symptoms : — , — , —
inflammatory
lung airway
reversible
obstruction
bronchospasm
allergen
dysponea ( labored breathing ) wheezing , cough
factors contributing to asthma:
1- Environmental Factors
—-, e.g. house dust mite, animal fur
Occupational, e.g. industrial —
—- (ozone, particulate matter)
2-Other Factors
Infections (particularly viral)
Pharmacological, eg — , —-
Exercise
Emotional stress
3-Genetic predisposition
—-, — interacting genes
- info:
Higher incidence of asthma
related to prevalence of PM
-Up to 1/3 of asthma cases
linked to PM exposure ( particle matter)
allergen
chemicals
air pollutant
aspirin , beta blocker
polygenic
multiple interacting genes
clinical feature of asthma :
Symptoms
Coughing,
—-,
Shortness of breath
Chest —
Tests
-Family History
-Physical Exam
- — (breath test)
- — tests
In more severe cases
- Xray/CT scan/Bronchoscopy
wheezing
chest tightness
spirometry
allergy test
pathophysiology of asthma:
—- of the air passages results in a — — of the airways which carry oxygen to lung
Airways Obstruction in asthma is due to;
- — inflammation
- —– bronchial smooth muscle hyperactivity
- increased — secretion
- — nerve over-activity
inflammation
temporary narrowing
pulmonary
bronchospasm
mucus
cholongeric
Pathophysiology of Asthma: Inflammatory response:
1- Initial Phase ( — )- Interaction of — with — cell — Release of — and —- aka —
2-Intermediate Phase ( —)- Release of — (IL-4, Il-5 IL-13) stimulating — release
3-Late phase (—) -influx of — lymphocytes, activating—- and— that release —- (e.g. eosinophil cationic protein) which cause damage to the lung—
minutes
allergen
mast cell IgE
histamine and PGD2
brocnhocontrction
hours
chemokines
leukocyte
days
Th2 lymphocyte
neutrophil and estinophil
toxic proteins
lung epithelium
so basically the pathophysiology of asthma relating to brocnhocntristion and inflammation:
1- abnormal response to —- leading to Lymphocyte Upregulation and Excess Production of Cytokines, IL-4, IL-6,
2- so — will be released from mast cells and also :
- minutes/early as Histamine
PGD2 LTC4, D4, E4 causes —-
3- hours/ intermediate as IL-4,5,6,8,13
GM-CSF
TNFa
causes — and mucosal —
4- days/ late as Leukotrienes
TNFa, IFN-g causes — and — activation and —- damage and bronchial —
allergen
Ige
broncoconsteiction
inflammation
mucosal oedema
neutrophil and estinophil
lung epithelium
bronchial hypersensitivity
Pathophysiology of Asthma - Autonomic Nervous System :
1-Parasympathetic:
—- innervation of airway smooth muscle — Nerve
Occupation of — receptors by —(released from – ) causes — .
2-Sympathetic:
No — sympathetic supply of smooth muscle.
Innervate —
When circulating adrenaline acts at —- on airway smooth muscle, it inhibits — .
predominant
vagus nerve
m3 receptors
ACH
vagus
bronchoconstriction ( basically ACh released from vagus nerve binds to M3 muscarinic receptors )
direct
blood vessels
b2 adrenorecpetor
bronchocontrsition
Activation of Vagus nerve, release — binds —
-M1located in — ganglia in airway, and M3located on airway — , mediate — via —
-M2receptors are located on — nerve endings and on smooth muscle and provide — feedback — release. counteract smooth muscle —.
Ach
m receptors
parasympathetic ganglia
smooth muscle
bronchoconstriction
Ach
cholinergic nerve endings
-ve
ACH
contraction
agents used in asthma:
Bronchodilators:
— adrenoreceptor —
— antagonists
- —
Anti-inflammatory Drugs:
—
—-
— synthesis inhibitors & receptor antagonists
b2 adrenoreceptor agonist
musarinic anatogonsit
xanthines
glucocorticoids
cromones
leukotrienes
b2 agonist:
Mechanism of Action
Bind —
Causes — of — smooth
muscle ( — ) by increasing
— via — linked activation of —
Inhibits mediator release from —
May also increase —-
Examples (SABA):
Short Acting (T1/2 — Hrs.)
—- (Ventolin)
Terbutaline
beta 2 adrenoreceptors
relaxation
bronchial smooth muscle ( bronchodilation )
cAMP
G protein
adenylate cyclase
mast cells
mucociliary clearance
2-3 hours
sulbutamol
b2 agonists: — Acting (T1/2 >—Hrs.) (LABA)
-Salmeterol / Formoterol / Indacaterol / Vilanterol
— acting compounds bind to an —site on the — receptor causing repeated — activation
Administration:
Inhaled as — or — ,
Rarely given — or —
Systemic Side Effects: —, —-, —-,
—-
info:
NB BETA BLOCKERS CAN PRECIPITATE ASTHMA-Contraindication
long
> 15 hours
long acting
exo site
b2 receptor
prolonged
powered or aerosols
orally or i/v
tremor , arrhythmia , hypokalemia , muscle cramp
muscarinic anatagonist:
Mechanism of action
Ipratropium (SAMA):
Inhibition of the action of—- at — , — , — muscarinic receptors, thus producing — and reducing
—- secretion.
—- acting than B2 agonists.
Tiotropium (LAMA):
— inhibition of — and — receptors
Examples Ipratropium Bromide –
Tiotropium Bromide
Umeclidinium Bromide newer long-acting agents
Administration:
Given by — –
not well — -little systemic effects
Side Effects- — tolerated
The most common side effects are — and —
acetyl choline
m1,m2,m3
bronchodilation
mucous secretion
slower
selective
m1 and m3
inhalation
absorbed
well
dry mouth and urinary retention
xanthines:
Mechanism of Action:
— bronchial smooth muscle (—) by inhibiting — resulting in increased — and — .
Also — actions (inhibit the — phase)
examples:
Caffeine
Theophylline
Taken – .
— half life
Sustained release preparations available
Aminophylline :
Taken by –
relax
bronchodilation
phospodiesterase
cAMP and cGMP
anti inflammatory
late
orally
short
IV
xanthines:
Side Effects
— therapeutic range (27-80mol/l)-
Side effects likely with concentrations >— mol/l
Gastrointestinal: — / —
Cardiovascular: — can be fatal
CNS: — , — , —
Pharmacokinetics
Metabolised in the —
— (CYP1A2) is the main isoform responsible for the metabolism (and inactivation) of theophylline
narrow
110
nausea / anorexia
arrhythmias
nervousness , tremor , seizures
liver
cytochrome p450
Pharmacokinetic Drug Interactions Occur with Theophylline because of — Metabolism by Cytochrome P450 Enzymes
Manydrugsinteractwiththeophyllineby inhibiting or potentiating its — by Cytochrome P450 isoenzyme (CYP1A2)
-rifampicin (an anti-tuberculosis drug) can increase Theophylline — by — Cytochrome P450 activity
- — and —- inhibit Cytochrome P450 activity, metabolism of theophylline, increasing theophylline —
-Both — and excessive — consumption can alter the blood levels of theophylline, which may affect the dosing.
-Note: – drug interactions are most important for drugs, such as theophilline, that have a – therapeutic index
extensive
metabolism
clearance
increasing
eythromycin and clarithromycin
toxicity
smoking and caffeine
pharmokinetics
low
check question 22 so imprtant
Corticosteroids in Asthma :
Mechanism of Action
-Overall Inhibition of — of Genes Coding — Involved in —
-Bind — receptor (GR) in the — , translocate to the — , and— genes via — e.g. Lipocortin-1 (Annexin) which inhibits —- , reducing inflammatory —
-Regulating pro-inflammatory transcription factors such as AP-1 and NF-kappa B preventing their binding to their gene target (transrepression) e.g.
COX 2, inflammatory and cytokine expression is inhibited
-END RESULT DECREASED —
transcription
cytokines
inflammation
systolic glucorticoides
systole
nuclease
transitive responsive
glucoticoides response element(GRE)
Phospholipase A2
prostaglandins
inflammation
corticosteroids used in asthma:
1- Inhaled ( — mode of administration)
Beclomethasone
Budesonide (extensive 1st pass metabolism in – )
Fluticasone ( — gut absorption)
Oral
Prednisolone
IV
Hydrocortisone
preffered
liver
poor
corticosteriods side effect:
Adrenal Suppression
Infections
Mineralocorticoid Effects
Hypertension
Fluid retention
Electrolyte imbalance
Structural Effects
Osteoporosis
Myopathy
Growth retardation (children)
Central Obesity
Metabolic Effects
Glucose intolerance
infection causes oral candidiasis ( thrush )
myopathy causes dysphonia or laryngeal muscles
both of these are the side effects in inhaled therapy
cromones:
Examples Sodium Cromoglycate & Nedocromil
Mechanism of action : —-
-Mast cell — –results in inhibition of — and reduced release of —
-Inhibition of —- reduced exaggerated neuronal reflexes triggered by irritant stimuli
-Inhibition of —- accumulation in lungs
Administration
Inhaled –— absorbed
Unwanted effects (few)
Few side effects, Cough and wheeze transiently post administration
— EFFECTIVE THAN STEROIDS
anti inflammatory
stabilisation
degranulation
mediators
sensory neuroses
estinophols
poorly
less
anti-leukotrienes:
2 sets of drugs targeting the Leukotriene pathway
1- Inhibitors of —- e.g. Zileuton which prevents leukotriene —
2- — antagonists such as Montelukast inhibiting — to leukotriene cysteinyl receptors
END UP WITH — and REDUCED —
Administration- —
Benefit seen in ~ — of patients. Most effective in
exercise induced bronchoconstriction (EIB)
cold induced bronchoconstriction
aspirin and NSAID induced bronchoconstriction
Not for — asthma attacks
— Side Effect profile
Headaches
Gastrointestinal upset
Rarely Churg Strauss Syndrome (inflammation of blood vessels)
lipoxygenase (LOX)
synthesis
leutokinre receptor
binding
bronchofilation
inflammation
oral
50%
acute
low
newer anti inflammatory approaches in asthma:
1- —- (Omalizumab) a monoclonal antibody used in patients with elevated serum levels of IgE
2- Benralizumab, sold under the brand nameFasenra, is amonoclonal antibodydirected against the —receptor(severe — asthma)
3-Reslizumab and Mepolizumab same mechanism
4-Studies have looked at
Anti-TNF-alpha agents (monoclonal antibodies)
Anti-inflammatory drugs
Methotrexate,
Allergen-Specific Immunotherapy
anti IgE
interlukin 5
estinophlic
management of acute asthma attack:
1- Quick Relief of — (Patient initiated)
- —- puffs of inhaled short acting — agonists as required for symptoms
- If more severe – up to — treatments at — minute intervals, or single nebulizer treatment
Course of oral prednisolone may be needed
2-Accident and Emergency Management of an Acute Severe Attack
Ensure adequate —
—-% oxygen via face mask
Nebulised b2 agonists (salbutamol)
Nebulised ipratropium
Oral prednisolone or IV hydrocortisone
3-If life-threatening consider
—- 2gm IV over 20 mins (Bronchodilator)
IV aminiphylline or salbutamol
Intubation and Ventilation (ICU)
bronchospasm
2-4 puffs
b2
3
20
hydration
40-60%
Magnesium sulphate
management of chronic ( long term ) asthma
STEP UP TREATMENT to CONTROL ASTHMA
STEP1: rapid acting beta agonist
STEP2: Reliever is rapid acting b-agonist and controller is low dose inhaled steroid or leukotrene modifier.. Montekelast/zileuton
STEP3; Reliever is the same inhaled steroid and long acting b-agonist or one of 3 other options (patient dependent)
STEP4: Reliever same, Medium dose steroid plus long acting beta agonist and one of 2 other options
CHRCK QUESION 36 PLS
summary :
1- Beta adrenergic receptor agonists, (Salbutamol), Short and Long Acting (SABA, LABA): Inhaled
MOA: Bind to the β2 adrenergic receptor in the smooth muscles in the lungs.
Activation of these G-protein coupled receptors increase, adenylate cyclase and cAMP concentrations which in turn leads to bronchodilation via Protein Kinase A
PKA phosphorylates intracellular targets leading to a decrease in calcium levels
resulting in the inhibition of myosin light chain phosphorylation preventing airway smooth muscle contraction.BRONCHODILATION Side Effects: Well Tolerated, rare side effects tremors
2-Muscarinic antagonists (Ipratropium), Inhaled, Short and Long Acting” SAMA, LAMA, Inhaled
MOA: block action of acetyl choline at M3 muscarinic receptors -Gq-coupled receptor that cause constriction in SMC via an increase in intracellular calcium,,
Bronchodilation, slower than Beta agonists
Side Effects: Well Tolerated, side effects -urinary retention
3- Xanthines (Theophylline), Oral mostly or IV,
MOA Inhibit phosphodiesterase (PDE ) enzyme
inhibition of tissue PDE increases cAMP by inhibition of cAMP breakdown Bronchodilation, wide ranging anti-Inflammatory effects
SE: Theophylline: Serious at high doses so monitor blood levels
Many drugs interact with theophyllineby inhibiting or potentiating itsmetabolism by CYP1A2 (induction of CYP1A2- rapidclearance of theophylline.
4- Glucocorticoids (Fluticasone) Inhaled preferred, Oral also (prednisolone)
MOA: Reducing Inflammation (trans activation/repression of anti/pro inflammatory genes)
Paper: Ramamoorthy S et al. Corticosteroids: Mechanisms of Action in Health and Disease. Rheum Dis Clin North Am. 2016 Feb;42(1):15-31
SE: Well tolerated inhaled, more serious SE oral
Anti-leukotrienes (Zileuton, Montekulast), Ingested orally
MAO: Leukotrienes are generated from arachidonic acid (AA) in multiple inflammatory cells:
Drugs work by inhibiting lipoxygenase (LOX) OR by inhibiting leukotriene binding to the Cysteinyl leukotriene receptors
SE: Well tolerated, Mild GIT effects nausea
