12. respa Flashcards
Cough is
a useful physiological mechanism
Is a protective reflex
Clear the respiratory passages of foreign material and excess secretions.
May be annoying and prevent rest and sleep.
Chronic cough can contribute to fatigue, especially in elderly patients.
Involves the………. and ………….., as well as the……… of the bronchial tree
cns pns and smooth muscle
pathogenesis of cough
Irritation of the bronchial mucosa bronchoconstriction stimulates cough receptors (stretch receptor) in tracheobronchial passages afferent fibers of the vagus nerve cough centers in the CNS (medulla)
cough occurs due to stimulation of …………. receptor in throat, respiratory passage or ………. receptors in the lungs.
mechanic- or chemoreceptor
stretch
Stimulation of sensory nerves in the epithelium by
secretions, foreign bodies, cigarette smoke and tumors
Sensitization of the cough reflex in which there is an abnormal increase in the sensitivity of the cough receptors demonstrable by inhalation of
capsaicin or hypotonic chloride solutions
Sensitization of the cough reflex presents clinically as a ………………………………………………………………………………….
persistent tickling sensation in the throat with paroxysms of coughing induced by changes in air temperature, aerosol sprays, perfumes and cigarette smoke.
sensitization associated with
association with viral infections, oesophageal reflux, postnasal drip, cough- variant asthma, idiopathic cough, and in 15% of patients taking ACE inhibitors.
Useless (non productive) cough:
stimulated by
Stimulated by inflammation in the respiratory tract or by neoplasia.
Should be suppressed to reduce frequency
Peripheral antitussives
MOA plus include
They suppress the irritated sensory nerve endings which initiates the cough reflex
They include:
Pharyngeal demulcents
Steam inhalation
Local anaesthetic
Dry cough is treated by antitussive drugs which are classified into :
Peripheral antitussives.
Central antitussives
Steam inhalation
e.g. tincture benzoin
One teaspoonful is added to a litre of boiling water and inhaled with the steam
It promotes the secretion of protective mucous
Pharyngeal demulcents
relieve cough due to?
MOA
include
e.g. liquorice lozenges
Relieve cough due to sore throat and pharyngitis
Smooth the throat (directly as well as promoting salivation) and Reduce afferent impulses from the inflamed irritated pharyngeal mucosa.
Thus provide symptomatic relief in dry cough arising from throat.
Drugs with local anaesthetic action
Benzonatate
Benzonatate isrelated to the local anesthethic
tetracaine
……….. anesthetizes the stretch receptors in the lungs, thereby reducing coughing.
Adverse reactions of benzonatate
include hypersensitivity, sedation, dizziness, and nausea.
Central antitussives
define moa plus includes
Act in the CNS to raise the threshold of cough center
Suppress the symptom without influencing the underlying condition.
opoids
non opoids
antihistamines
central antituissives Can cause harmful
sputum thickening and retention
They should not be used for the cough associated with asthma
Opioids
include
why these
Codeine, Pholcodeine
Less addiction liability than the main opioid analgesics and is an effective cough suppressant.
It also decreases secretions in the bronchioles, which thickens sputum and inhibits ciliary activity
drying action on the respiratory mucosa may be ………………..or ………………………….
useful (eg, in bronchorrhea) or deleterious (eg, when bronchial secretions are already viscous)
opoids excretes its action through
mu opioid receptors in the brain.
side effects of opiods
constipation
drowsiness
respiratory depression
codeine metabolism
codein prodrug
to
codeine 6 glucoronide by UGT2B7
Morphine CYP2D6
Non opioids
include
moa
potency with codein
but makes it better by
Dextromethorphan
Has selective antitussive action (raises threshold of cough center) by blocking NMDA receptors
Its antitussive potency is equivalent to that of codeine and it produces only marginally less constipation and inhibition of mucociliary clearance
side effects of dextrometrophan
Has got side effect like, dizziness, nausea, drowsiness, and ataxia.
dextrometrophan metabolism
by hepatic first pass to dextrophan whic has less effect on CNS
Antihistamines include
receptor type?
moa
which generation
Many H1 antihistamines have been conventionally added to antitussive (expectorant) formulation.
They offered relief in cough due to their sedative and anticholinergic action, but lack selectivity for cough center.
first generation
Useful (productive) cough:
Serves to drain the air way
Its suppression is not desirable, may be even harmful, except if the amount of expectoration achieved is small compared to the effort of continuous coughing
Expectorants are used for
They increase bronchial secretion or reduce its viscosity, facilitating its removal by coughing.
They are believed to “loosen” cough which becomes less tiring and more productive.
types of expectorants
direct acting
stimulant
mucolytic
Directly acting:
include
MOA
Sodium and Potassium citrate or acetate, potassium iodide, Guanacol, and
Guaifenesin
They increase bronchial secretion by salt action.
Stimulant expectorants
include
MOA
They stimulate healing and repair of chronically inflammed respiratory mucosa.
They decrease the amount of sputum and have mild antiseptic action .
They include:
- Creosote 0.1 - 0.6 Tid
- Terpene hydrate 0.3 g. Tid
side effects of mucolytics
lachrymator, gastric irritant and hypertensive action
Mucolytics
include
moa
Bromhexine, Carbocisteine, Acetyl cytokine and Ambroxol
they depolymerizes monopoly saccharine directly as well as liberating lysosome enzymes – net work of fibers in tenacious sputum is broken.
Rhinitis
plus type
iswhen a reaction occurs that causes nasal congestion, runny nose, sneezing, and itching
seasonal
perennial
seasonal rhinitis
symptoms
may develop
This is often called ‘hayfever’ and is the most common of all allergic diseases.
Nasal irritation, sneezing and watery rhinorrhoea are the most troublesome symptoms
asthma
in rhinitis itching of the eyes and soft palate and occasionally even itching of the ears because
of the common innervation of the pharyngeal mucosa and the ear.
Patients with perennial rhinitis rarely have symptoms that affect the ………..
eyes or throat.
Half have symptoms predominantly of sneezing and watery rhinorrhoea, whilst the other half complain mostly of nasal blockage.
The patient may lose the sense of smell and taste.
A swollen mucosa can obstruct drainage from the sinuses, causing
sinusitis in half of the patients.
Pathogenesis of perennial rhinitis
Sneezing, increased secretion and changes in mucosal blood flow are mediated both by efferent nerve fibres and by released mediators
Mucus production results largely from ………..stimulation, while blood vessels are under ……………..
parasympathetic
both sympathetic and parasympathetic control.
Sneezing, largely caused by histamine, results from stimulation of ………nerve endings and begins within minutes of the allergen entering the nose.
afferent
Allergic rhinitis develops as a result of interaction between the inhaled allergen and adjacent molecules of IgE antibody present on the surface of mast cells found in increased numbers in nasal secretions and within the nasal epithelium.
Release of preformed mediators, in particular histamine, causes an increase in permeability of the epithelium, allowing allergen to reach IgE-primed mast cells in the lamina propria.
drugs for rhinitis
antihistamins
decongestans
corticosteriods
The……………. and ……………..released from mast cells, eosinophils and macrophages are especially potent in causing nasal blockage.
cysteinyl leukotrienes and vasodilator prostaglandins (PGD2, PGE2 and PGI2)
anti histamins
best for which symptom and less effective for which symptom
Antihistamines remain the most common therapy for rhinitis
They are particularly effective against sneezing
Less effective against rhinorrhoea and have little influence on nasal blockage.
The first-generation antihistamines cause sedation.
Second-generation drugs
cetirizine (10 mg once daily), loratadine (10 mg once daily), desloratadine (5 mg daily) and fexofenadine (120 mg daily) are highly specific for H1, receptors
Fatal cardiac arrhythmias (torsades de pointes) have been described with
terfenadine and astemizole.
Antihistamines also control
Antihistamines also control itching in the eyes and palate.
Decongestants
moa
work well with combination with
Decongestants are sympathomimetic agents that act on adrenergic receptors in the nasal mucosa, producing vasoconstriction.
Decongestants shrink swollen mucosa and improve ventilation.
When nasal congestion is part of the clinical picture, decongestants work well in combination with antihistamines.
types of decongestants
topical
and
systemic
topical decongestants
include
are applied directly to swollen nasal mucosa via drops or sprays.
Short-acting
Phenylephrine hydrochloride
Intermediate-acting
Naphazoline hydrochloride
Tetrahydrozoline hydrochloride
Long-acting
Oxymetazoline hydrochloride
Xylometazoline hydrochloride
Prolonged use of these agents (for more than 3 to 5 days) can result in a condition known as
rhinitis medicamentosa, or rebound vasodilation, with associated congestion.
Combining the weaning process with ………… is useful.
nasal steroids
Systemic Decongestants.
types
pseudoephedrin and oral form of phenylephrine
and
Sodium cromoglicate and nedocromil sodium
Adverse effects
of topical decongestants
include burning, stinging, sneezing, and dryness of the nasal mucosa.
pseudoephedrin and oral form of phenylephrine
effectiveness
lasts?
safe?
Are not as effective on an immediate basis as the topical agents
Their effects last longer and they cause less local irritation.
Pseudoephedrine can cause mild central nervous system stimulation
why
Doses of …. mg pseudoephedrin have been shown to produce no measurable change in blood pressure or heart rate.
In higher doses (…….), pseudoephedrine has raised both blood pressure and heart rate.
180
210-240
Sodium cromoglicate and nedocromil sodium
moa
They act by blocking an intracellular chloride channel and preventing cell activation.
Sodium cromoglicate applied topically
The most effective treatment for rhinitis is to use small doses of
topically administered corticosteroid preparations (e.g. beclometasone spray twice daily or fluticasone propionate spray once daily).
The amount used is insufficient to cause systemic effects and the effect is
primarily anti-inflammatory.
Bronchial asthma
is
Is characterized by hyperresponsiveness of tracheo-bronchial smooth muscle to variety of stimuli
when should we start corticosteroids
Preparations should be started prior to the beginning of seasonal symptoms.
The combination of a………………………………………………………………………………. taken regularly is particularly effective.
topical corticosteroid with a non-sedative antihistamine
If other therapy has failed, seasonal and perennial rhinitis respond readily to a short course (2 weeks) of treatment with
oral prednisolone 5-10 mg daily..
It may be necessary to use an …………………………………….. to decongest the nose prior to taking the topical corticosteroid.
alpha-1 adrenergic agonist
Results in narrowing of air tubes, often accompanied by increased secretion, mucosal edema and mucus plugging.
athsma patients present with
It causes shortness of breath, cough, chest tightness, wheezing and rapid respirations.
In addition to airway obstruction, cardinal features of asthma include
inflammation and hyperreactivity of the airway.
Bronchial asthma
Is characterized by hyperresponsiveness of tracheo-bronchial smooth muscle to variety of stimuli
Factors that contribute to airway obstruction in asthma
Contraction of the smooth muscle that surrounds the airways
Excessive secretion of mucus and in some, secretion of thick, tenacious mucus that adheres to the walls of the airways
Based on the underlying pathophysiology of the disease, anti-inflammatory therapy must be used in conjunction with bronchodilators in all but…..,..
the mildest asthmatics
Primary classes of antiasthma drugs are
bronchodilators and antiinflammatory agents.
Drug groups in Asthma
7
-adrenergic receptor agonists
Anticholinergics
Methylxanthines
Glucocorticoids
Leukotriene inhibitors
Chromones mast cell stabilizer
Anti-immunoglobulin E (IgE)
Sympathomimetic, Methylxanthines and Anticholinegics are commonly called
bronchodilators
Approaches to Treatment 7
Prevention of AB:AG reaction
Avoidance of antigen, hyposensitization if antigen can be identified.
Suppression of inflammation and bronchial hyperactivity.
Corticosteroids
Prevention of release of mediators.
Mast cell stabilizers
E.g. Sodium cromoglycate (Cromolyn sod.)
Antagonism of released mediators.
leukotriene antagonist
E.g. Montelukast and Zafirlukast
Antihistamines
Blockade of constrictor neurotransmitter
Anticholinergics
E.g. Atropine, Ipratropium
Mimicking dilator neurotransmitter
Sympathomimetics
E.g. Adrenaline, Ephedrine, Salbutamol, Terbutaline, Bambuterol, Salmeterol, Formoterol.
Directly acting bronchiodilators
Methylxathines
E.g. Theophylline
The sympathomimetics have several pharmacologic actions that are important in the treatment of asthma.
like
3
They relax airway smooth muscle
Inhibit release of bronchoconstricting mediators from mast cells.
They inhibit microvascular leakage and increase mucociliary transport by increasing ciliary activity.
B-adrenergic receptor agonists
selectivity?
classification
Selective 2-receptor agonists
They are mostly delivered directly to the airways via inhalation.
Classified as
Short-acting agonists: used only for symptomatic relief of asthma
Long-acting agonists: used prophylactically in the treatment of the disease.
MOA of B2 AR agonists
activates adenylate cyclase consequently increasing cytosolic cAMP bronchial relaxation
Long-term exposure to 2-agonists may desensitize some of these receptor-response pathways
β-Adrenoceptor-mediated airway smooth muscle relaxation. Rho-kinase normally phosphorylates and thus inhibits myosin phosphatase, favoring contraction. In
the presence of β-adrenoceptor agonists, increased cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) inhibit RhoA, which inhibits Rho-kinase, increasing
the activity of myosin phosphatase. The net result is dephosphorylation of myosin light chain20 and relaxation.
Short-Acting 2-AR Agonists
include
route
onset
duration
Drugs in this class include albuterol, levalbuterol, metaproterenol, terbutaline, and pirbuterol.
Used for acute inhalational treatment of bronchospasm, though some are also used orally.
Inhalation drugs has rapid onset of bronchodialation (1-5 min) which lasts for about 2 to 6 hours
…………………….Are the preferred treatment for rapid symptomatic relief of dyspnea associated with asthmatic bronchoconstriction.
short term b agonist
Long-Acting B2-AR Agonists
include
dilation last how many hours?
and why
Drugs in this class include Salmeterol and formoterol
Bronchodilation lasts over 12 h with inhalation salmeterol
The higher lipophilicity of the drugs may be responsible for the extended effect
Chronic use leads to receptor desensitization and a diminution of effect
long term B2 agonist More pronounced in -AR on ……………………than that on ………………………….
inflammatory cells
bronchial smooth muscle.
Oral Therapy with B-AR Agonists
is used in 2 situations
plus the drus
In children (< 5 yrs) who can not manipulate metered-dose inhalers (albuterol or metaproterenol syrups)
In some severe asthma exacerbations, aerosols can worsen cough and wheezing by causing local irritation
Methylxanthines
include
MOA
Theophylline, ……. tea,
Theobromine, …….. cocoa
Caffeine. …… coffee
At high concentrations, they inhibit several members of the phosphodiesterase (PDE) enzyme.
methylxanthines inhibit which PDE
plus what
The inhibition of PDE4 in inflammatory cells reduces the release of cytokines and chemokines
decrease in immune cell migration and activation
The inhibition of PDE4 in inflammatory cells reduces the release of cytokines and chemokines
decrease in immune cell migration and activation
margin of safety of methylxanthines
plus side effects
narrow margin of safety
Adverse effect is primarily to GIT, CNS and CVS.
CNS effects of methylxanthines in differents doses
In low and moderate doses;
mild cortical arousal with increased alertness and deferral of fatigue.
The larger doses
cause nervousness and tremor in some patients ( dose that is necessary for bronchodiltion).
Very high doses,
cause medullary stimulation and convulsions
CVS effects of methylxanthines
plus viscosity
Have positive chronotropic and inotropic effects.
The clinical expression of these effects on cardiovascular function varies among individuals.
In sensitive individuals, consumption of a few cups of coffee may result in arrhythmias.
Methylxanthines decrease blood viscosity and may improve blood flow under certain conditions.
methylxanthine effects on GIT and kidney
Stimulate secretion of both gastric acid and digestive enzymes.
However, even decaffeinated coffee has a potent stimulant effect on secretion, which means that the primary secretagogue in coffee is not caffeine.
are weak diuretics.
This effect may involve both increased glomerular filtration and reduced tubular sodium reabsorption.
In addition to their effect on airway smooth muscle, these agents - in sufficient concentration - inhibit antigen-induced release of histamine from lung tissue
methylxanthines
Effects on skeletal muscles
methyl xanthine
Strengthen the contractions of isolated skeletal muscle in vitro and improve contractility and reverse fatigue of the diaphragm in patients with COPD.
theophylline Improvement in pulmonary function is correlated with plasma concentration in the range of
5_20 mg/L.
Anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety occur at concentrations of …..mg/L in some patients and become common at concentrations greater than…….. mg/L.
15
20
Higher levels (40 mg/L) may cause :
theophylline
seizures or arrhythmias;
These may not be preceded by gastrointestinal or neurologic warning symptoms.
anticholinergic include
Muscarinic antagonists competitively inhibit the effect of acetylcholine at muscarinic receptors.
M3
Atropine
Ipratropium bromide
Leukotriene antagonists include:
Inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis;
Zileuton, a 5-lipoxygenase inhibitor
Inhibition of the binding of LTD4 to its receptor on target tissues, thereby preventing its action.
Zafirlukast and Montelukast
Adverse effects of leukotriene inhibitors
Zafirlukast and Montelukast
Rare incidences of systemic eosinophilia and a vasculitis
Zileuton
Liver enzymes elevated, generally within the first 2 months of therapy.
Decreases clearance of theophylline and warfarin clearance.
Pharmacokinetics of leukotriene inhibitors
absorbtion
bioavailability
proteinbound
half life
Pharmacokinetics
Zafirlukast
absorbed rapidly, with greater than 90% bioavailability.
Over 99% protein-bound
Its half-life is approximately 10 hours.
Montelukast
is absorbed rapidly, with about 60% to 70% bioavailability.
It is highly protein-bound (99%).
Its half-life is between 3 and 6 hours.
Zileuton
is absorbed rapidly on oral administration.
It is a short-acting drug with a half-life of approximately 2.5 hours
is highly protein-bound (93%).
Their principal advantage is that they are taken orally; some patients - especially children - comply poorly with inhaled therapies.
Chromones define plus include
mast cell stabilizer
Cromolyn Sodium (Disodium Cromoglycate) and Nedocromil sodium.
what effectively inhibit both antigen-and exercise-induced asthma
chromones
cromolyn…….
medocromil………
how takes
Cromolyn ……..must be inhaled as a microfine powder or aerosolized solution.
Nedocromil ..….is available only in metered-dose aerosol form.
Cromolyn solution is also useful in reducing symptoms of
allergic rhinoconjunctivitis
chromones inhibit what
Release of Histamine, LTS, Interlukines e.t.c. from mast cells as well as other inflammatory cell is prevented and Chemotaxis of inflammatory cells is inhibited.
when are chromones takes
prophylactically
side effects of chromones include
Include such as throat irritation, cough, and mouth dryness, and, rarely, chest tightness, and wheezing.
Serious adverse effects are rare.
Reversible dermatitis, myositis, or gastroenteritis, pulmonary infiltration with eosinophilia and anaphylaxis have been reported.
lack of toxicity of chromones accounts for
cromolyn’s widespread use in children, especially those at ages of rapid growth.
MoA of glucocorticoids in Asthma
The antiinflammatory effects of glucocorticoids in asthma include
Modulation of cytokine and chemokine production
Inhibition of eicosanoid synthesis
Marked inhibition of accumulation leukocytes in lung tissue
Decreased vascular permeability
Upregulation of -adrenoceptor number
glucocorticoids effect on airway obstruction may be due in part;-
Contraction of engorged vessels in the bronchial mucosa
Potentiate the effects of β-receptor agonists,
Inhibit the lymphocytic, eosinophilic mucosal inflammation of asthmatic airways.
types of corticosteroids for asthama
oral
predinisone and methylpredinison
oral corticosteroids
parentral
inhatd
Inhaled corticosteroids are used for maintenance treatment of asthma as……………
because
prophylactic therapy
Inhaled corticosteroids are not effective for relief of acute episodes of severe bronchospasm
An average daily dose of four puffs twice daily of beclomethasone (400 mcg/d) is equivalent to about 10-15 mg/d of oral prednisone , with far fewer systemic effects.
one of the cautions in switching patients from oral to inhaled corticosteroid therapy is to taper oral therapy slowly to avoid
precipitation of adrenal insufficiency.
Adverse Effects and Contraindications
Systemic administration of the corticosteroids
Adrenal suppression, cushingoid changes, CNS effects and behavioral disturbances , increase susceptibility to infection
Increase the risks of osteoporosis and cataracts over the long term
In children, growth retardation, but this effect appears to be transient
……………………Are either poorly absorbed or rapidly metabolized and inactivated and thus have greatly diminished systemic effects relative to oral agents.
inhaled corticosteroids
adverse effects of inhaled corticosteroids
Oropharyngeal candidiasis.
hoarseness of the vocal cords.
sore throat and throat irritation,
and coughing.
The risk of this complication of oropharyngeal candidiasis can be reduced by
having patients gargle water and spit after each inhaled treatment.
solution for side effect of inhaled -hoareness
Special delivery systems (e.g., devices with spacers) can minimize these side effects.
Anti-IgE therapy name
omalizumab
Pharmacokinetics and Metabolism
route
every what days
bioavailabilty
halflife
where eliminated
Delivered as a single subcutaneous injection every 2 to 4 weeks.
It has a bioavailability of about 60%.
The serum elimination half-life is 26 days.
The elimination of omalizumab-IgE complexes occurs in the liver.
Some intact omalizumab is also excreted in the bile.
Adverse effects
of omalizumab
Generally well tolerated.
Most frequent adverse effects: injection-site reactions (e.g., redness, stinging, bruising, and induration), anaphylaxis was seen in 0.1% of treated patients.
Possibly malignancies
treatment for quick relief of asthma
1.adreneregic stimulants
Catecholamines(E,NE,isopretenol)
Resorcinols(terbutaline)
Saligenins(albuterol) respiratory selective, less cardiac effect
G-protein/cAMP→↓release of mediators/increased mucocilliary
Short acting-30-90 min
- Mythylxanthines
Theophylline-medium potency, aminophylline
3.Anticolinergics iprathropium-in CHF(others contraindicated, but slow 60-90 min
Long term treatment
of asthma
For long term treatment two cases of medicine are required:
- inhaled corticosteroids
- short acting B2-agonists
Inhaled medicine most conveniently administered using metered-dose inhalers
Components of COPD
Chronic Bronchitis
Emphysema
Asthma (?)
Although not strictly a COPD disorder asthma is often
linked with being a COPD disorder.
Risk factors
for COPD
Cigarette smoking-pack year(dose X years) ↓FEV1 faster
Airway responsive as in asthma(genetic predisposition)
Respiratory infections-childhood(initiate/exacerbate)
Occupational exposure-dust,gold,↓FEV1
Air pollution town>rural,↑Women( indoor pollution)
+/_ genetic /environmental+passive
Genetic –α1 antitrypsin deficiency(emphysema)
