7 The afferent limb includes receptors within the sensory distribution of the trigeminal, glossopharyngeal, superior laryngeal, and vagus COUGH Cough is a powerful physiological mechanism that causes the central airways to be cleared of foreign material and excess secretion It is characterized by a violent expiration, which provides the high flow rates that are required to shear away mucus and remove foreign particles from the larynx, trachea, and large bronchi. Most sensory stimuli that cause coughing also increase airway secretion, which is beneficial as this provides a vehicle for expulsion of particulate matter. Cough Receptors Cough usually results from the stimulation of sensory nerves in the airways. The nerves that initiate cough are predominantly in the upper airway, for it is here that the greatest protection against the ingress of foreign material is required. The sensor and central components of the reflex arc are targets for drugs that suppress cough: • Through reducing receptor activation or activity in the afferent nerves • Reducing sensitivity of the ‘cough center’ As a reflex mechanism, the cough involves an arc with central, sensory and efferent components. The exact nature of the sensory receptors of cough are unknown. Anatomically, cough sensitive nerves extend from the larynx to the division of the segmental bronchi. The exact pathway of the Subject: Pharmacology Topic: Antitussives Lecturer: Dra. Aguinaldo Date of Lecture: October 2, 2011 Transcriptionist: The Soloist SY 2011-2012
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The afferent limb includes receptors within the sensory distribution of the trigeminal, glossopharyngeal, superior laryngeal, and vagus nerves
COUGH
Cough is a powerful physiological mechanism that
causes the central airways to be cleared of foreign
material and excess secretion
It is characterized by a violent expiration, which
provides the high flow rates that are required to
shear away mucus and remove foreign particles
from the larynx, trachea, and large bronchi.
Most sensory stimuli that cause coughing also
increase airway secretion, which is beneficial as this
provides a vehicle for expulsion of particulate
matter.
Cough Receptors
Cough usually results from the stimulation of
sensory nerves in the airways.
The nerves that initiate cough are predominantly in
the upper airway, for it is here that the greatest
protection against the ingress of foreign material is
required.
The sensor and central components of the reflex arc
are targets for drugs that suppress cough:
• Through reducing receptor activation or
activity in the afferent nerves
• Reducing sensitivity of the ‘cough center’
As a reflex mechanism, the cough involves an arc
with central, sensory and efferent components.
The exact nature of the sensory receptors of cough
are unknown. Anatomically, cough sensitive nerves
extend from the larynx to the division of the
segmental bronchi. The exact pathway of the
afferent pathways involved in cough and the exact
location of the CNS relay (cough center) are also
unknown.
The efferent pathway for cough involves the
intercostal and phrenic nerves. Abrupt contraction
of the respiratory muscles leads to an explosive rise
in intrathoracic pressure, which forces air out of the
alveoli and through the airways.
Subject: PharmacologyTopic: AntitussivesLecturer: Dra. AguinaldoDate of Lecture: October 2, 2011Transcriptionist: The SoloistPages: 8
SY 2
011
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12
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The vagus nerves are known to carry the sensory
information from the lung which initiates the cough
reflex, as cough from stimulation of one side of the
bronchial tree is abolished by ipsilateral vagotomy.
The lung has three types of sensory nerves: slowly
adapting stretch receptors, rapidly adapting
stretch receptors (or "irritant receptors"), and C
fibre endings. The latter are subdivided into
pulmonary C fibre endings and bronchial C fibre
endings, depending on the source of their blood
supply.‘ Cough caused by mechanical irritation
results from stimulation of myelinated or non
myelinated sensory nerves in the larynx or the
rapidly adapting stretch receptors in the lung, or
both. Cough caused by direct chemical stimulation
results from activation of receptors in the larynx
(myelinated or non-myelinated) or activation of C
fibre endings in the lung, or both.
The four phases of cough
The prevalence of cough in the population depends on the prevalence of smoking and other environmental factors and in different populations has varied from 5% to 40%. One indication of the size of the problem is the self prescription of over the counter antitussives, which has been estimated at 75 million doses per annum in the United Kingdom.
*TYPES OF COUGH
1. ACUTE COUGH: lasts less than 3 weeks
CAUSES: Upper respiratory infections i.e. common cold, acute bacterial sinusitis, pertussis, exacerbations of COPD, allergic rhinitis and rhinitis due to environmental irritants
NOTE: Estimating the duration of cough is the first step in narrowing the list of possible diagnoses.
Treatment for Acute Cough
Cause Therapeutic option Common cold Dexbrompheniramine
6mg, plus pseudoephedrine, 120 mg daily for 1 week or naproxen 500mg LD then 500mg TID x 5 days, or ipratropium nasal spray 2 sprays per nostril 3-4x/d as needed for 4 days
Allergic rhinitis Avoidance of allergens; Loratidine 10mg OD
Acute bacterial sinusitis Dextropheniramine + pseudoephedrine BID x 1 week; Oxymetazoline 2 sprays daily OD x 5 days; Treat for H. influenzae and S.pneumoniae
Exacerbation of COPD Antibiotic vs. H. influenzae and S. pneumoniae; Systemic corticosteroids tapered over 2 weeks; continous oxygen as needed;
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Ipratropium + albuterol, cessation of smoking
Bordetella pertussis infection
Erythromycin 500mg QID x 14 days or if allergic, Co-tri 160-800mg BID x 14 days
MOA: Guaifenesin increases the volume and reduce the viscosity of tenacious sputum and is used as an expectorant for productive cough.
PK: Absorption: Well absorbed in the GI tract.Excretion: Urine.
Adverse effects: GI discomfort, nausea and vomiting; dizziness, drowsiness, headache; rash; decreased uric acid levels; urinary calculi (large doses).
BROMHEXINE
Classification: Mucolytic
Dose: PO 8-16 mg 3 times/day. Should be taken with food
MOA: secretolytic, causes increase in the production of serous mucus in the respiratory tract and makes the phlegm thinner and less sticky. This contributes to a secretomotoric effect: it helps the cilia to transport the phlegm out of the lungs.
Adverse effects: GI side effects; headache, dizziness, sweating, skin rashes. Inhalation: Cough or bronchospasm; transient rise in aminotransferase values
Adverse effects: Mild GI effects and allergic reactions.
CODEINE
Classification: Narcotic, centrally acting
Dose: (cough suppression)
Adult: 15-30 mg 3-4 times daily. Max: 240 mg/day.Child: 1-5 yr: 3 mg; 5-12 yr: 7.5-15 mg. Doses to be taken 3-4 times daily. Renal impairment: Dose adjustment may be needed.Hepatic impairment: Dose adjustment may be needed.
MOA:Codeine provides relief by blocking the ascending pain pathways by binding to opiate receptors found in the CNS. It also helps suppress cough by direct action in the medulla.Onset: Oral: 0.5-1 hr. IM: 10-30 min.Duration: 4-6 hr.
PK: DRUG PROTOTYPES
Absorption: Oral and rectal: Adequate.Distribution: Crosses placenta and enters breast milk.Metabolism: Hepatic by O- and N-demethylation to morphine (active), norcodeine and other metabolites including normorphine and hydrocodone.Excretion: In the urine, mainly as conjugates with glucuronic acid. Plasma half-life: about 3-4 hr.
Adverse effects: CNS and respiratory depression, seizures in infants,
bradycardia,hypotension, potential for abuse and dependence
• Indication: Symptomatic relief of cough, best when cough is nonproductive (depresses medullary cough center).
POTENTIAL FUTURE ANTITUSSIVE THERAPIES
1. VR1- Vanilloid Receptor Antagonists
Used capsaicin to identify these receptors
2. Selective Opioid Receptor Agonists
3. Opioid –like Receptor Agonists
• Agonists of the µ-opioid receptor (such as codeine) suppress cough at the expense of adverse effects that may include sedation, respiratory depression, nausea, constipation, and potential for abuse.
• A more specifically acting agent that could inhibit cough without such undesirable side effects would offer significant benefit over the currently available narcotic antitussive agents
4. Tachynin Receptor Antagonists
• In human airways, inflammatory cells appear to be the major source of tachykinins, which include various neuropeptide transmitters such as substance P, neurokinin (NK) A, NKB, and calcitonin gene-related peptide.
• Animal studies have suggested that tachykinins, through stimulation of three receptor subtypes (ie, NK1, NK2, and NK3), induce neurogenic inflammation, bronchial hyperresponsiveness,and cough.
Antagonists of the three NK receptor subtypes have been isolated and have demonstrated antitussive activity in animal studies.
5. 5-Hydroxytryptamine Receptor Agonist
• 5-Hydroxytryptamine (5-HT) has been demonstrated to suppress experimentally induced cough in healthy volunteers
• Animal studies have demonstrated that the modulation of potassium channels can inhibit experimentally induced cough
• Further elucidation of the role of potassium channels in pathologic cough may yield effective therapeutic agents in the future.
NOTE: Multiple studies have shown that antitussive therapy is highly successful if aimed at specific etiologies of cough. In cases wherein there is a need for non-specific therapy, such as in chronic unexplained cough, current antitussive therapy may be inadequate or have unacceptable side effects.
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