7

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

-20

12

7

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;

7

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

2. SUBACUTE COUGH: lasts from 3-8 weeks

CAUSES: post infectious cough, subacute bacterial

sinusitis, bordetella pertussis, asthma

Treatment for Subacute Cough

Treatment for Chronic Cough

Causes Therapeutic options Postnasal drip syndromes: Non-allergic rhinitis

Dexbrompheniramine + pseudoephedrine x 3 weeks or ipratropium nasal spray for 3 weeks

Allergic rhinitis Avoidance of offending allergens; Loratidine 10 mg BID

Vasomotor rhinitis

Ipratopium nasal spray x 3 weeks then as needed

Chronic bacterial sinusitis

Dexbropheniramine+ pseudoephedrine for 3 weeks; oxymetazoline for 5 days;specific antibiotic therapy ( H. influenzae, Strep and anaerobes)

Asthma Beclomethasone and albuterol as metered dose inhaler

GERD Modifications of diet and lifestyleAcid suppressionProkinetic therapy

Chronic Bronchitis Elimination of irritant; Ipratropium by metered dose inhaler

ACE inhibitors Discontinuance of the drug

Eosinophilic bronchitis

Inhaled budesonide 400µg BID x 14 days

Cause Therapeutic option Postinfection Dexbrompheniramine

+ pseudoephedrine x 1 week or ipratropium nasal spray x 1-3 weeks; systemic corticostreroids tapered over 2-3 weeks; central antitussives

B. Pertussis infection

Erythromycin x 14 days or Co-trimoxazole

Subacute bacterial sinusitis

Dexbrompheniramine + pseudoephedrine x 3 weeks; Oxymetazoline x 5 days; antibiotics

Asthma Beclomethasone, albuterol

3. CHRONIC COUGH : lasting more than 8 weeks

CAUSES: post-nasal drip syndromes (most

common), chronic bacterial sinusitis, asthma,

gastroesophageal reflux disease (GERD), chronic

bronchitis, angiotensin-converting enzyme

(ACE) inhibitors, eosinophilic bronchitis.

COUGH MEDICATIONS

Non-specific or Suppressant Therapy:

- Drugs that bind to specific pharmacologic

receptors affecting on well-defined areas of the

CNS and peripheral NS.

- Intended to reduce coughing regardless of

etiology

- Used when the excitability &/or intensity of

the cough is elevated over what is required to

defend the airways

CLASSIFICATION:

A.Peripherally Acting

Refer to drugs that modify the excitability of the

cough receptors. Usually non-sedating. Involves

the suppression of pulmonary afferent activity.

1. Antihistamines

Examples: Diphenhydramine HCl, Fenspiride

Proposed MOA:

- may have an indirect effect on the cough mechanism, it may reduce postnasal drip which can precipitate cough

- H1 antagonists

- inhibit mast cell release of Histamine and other inflammatory mediators

First generation: More sedating, more anticholinergic activity

Second generation: Less sedating owing in part to lesser distribution in the CNS and little or no anticholinergic activity

2. Expectorants

Examples: Potassium Cl, Ammonium Cl, Syrup of Ipecac, Glyceryl guaiacolate

Proposed MOA:

- may lead to more coughing

- may alter the physicochemical properties of mucus or its secretion rate.

- may also have an effect on the chemotactic trigger zone in the midbrain

3. Mucolytics

Examples: Acetylcysteine,Carboxymethylcysteine, Bromhexine, Ambroxol HCl, Erdosteine

MOA:

breaks disulfide bonds that hold mucus together thus facilitating easier expulsion.

Precautions: in treating bronchospasms, in patients with other underlying problems i.e. peptic ulcers and esophagel varices

4. Bronchodilators

• Examples: Ephedrine, Theophylline, Terbutaline

• Role in cough suppression in the absence of asthma èconflicting results in studies done.

• The use of anti asthmatic drugs to treat cough in the absence of asthma is not recommended

Possible MOA :

? Reduce input from stretch receptors and cause bronchodilation even in normal airways

? May alter mucociliary clearance

5. Demulcents

Examples: Syrup of Acacia, Glycerin, Licorice (glycyrrhizin), Honey, Olive Oil

Proposed MOA:

-the sugar in the cough mixture encourages saliva production èswallowing may interfere with the cough reflex

- the sugar solution may coat the sensory nerve endings in the epipharynx which may result in cough suppression

- the sugar coating may act as a protective barrier to the sensory receptors that produce cough.

6. Local Anesthetics

Examples: Benzocaine, Benzonatate

Proposed MOA:

- has an effect on unmyelinated and myelinated nerve endings

- may remove all protective reflexes and cause bronchoconstriction

- may act on the C fibers

B.Centrally Acting cough medications

Refer to drugs that act on the sensory afferents that control the excitability of the neural elements in the brainstem that produce cough.

May be sedating.

CLASSIFICATION:

1. Narcotic

Codeine

Acts on sensory nerve endings that produce cough; µ receptors in the lung, exact location ?

they act within the CNS either a direct action on the cough center in the medulla or in the brainstem respiratory center

-µ receptor stimulation may lead to increase mucociliary clearance or decrease mucus production, hence reduce the need for cough

1. Non-narcotic

Dextromethorphan Hbr

Butamirate citrate

Dimethoxanate

Pipazethate

DRUG PROTOTYPES

GLYCERYL GUAIACOLATE/ GUAIFENESIN:

Classification: Expectorant

Dose:Adult: 200-400 mg every 4 hr. Max: 2.4 g/day. Child: 6-12 yr: 100-200 mg;

2-6 yr: 50-100 mg;

6 mth-2 yr: 25-50 mg.

To be given every 4 hr.

Max: 6-12 yr: 1.2 g/day; 2-5 yr: 600 mg/day.

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

AMBROXOL HCL

Classification: Mucolytic

Dose:Adult: 60-120 mg daily, in 2-3 divided doses. Child: <2 yr: 7.5 mg bid;

2-5 yr: 7.5 mg bid/tid;

6-12 yr: 15 mg bid/tid. Taken with food.

MOA: a metabolite of bromhexine hence same action

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

DEXTROMETORPHAN HYDROBROMIDE

Classification & MOA: Non-Narcotic, centrally acting

• Dose: Children 2–6 yr: 2.5–7.5 mg q 4–8 hr or extendedrelease, 15 mg q 12 hr (max: 30 mg/24 hr).

• 6–12 yr: 10–15 mg q 4–8 hr, or extended-release, 30 mg bid (max: 60 mg/24 hr).

• >12 yr and adults: 10–30 mg q 4–8 hr, or extended release, 60 mg bid (max: 120 mg/24 hr).

Adverse effects in OD:

N/V, drowsiness, unsteadiness, visual disturbances, difficulty breathing, tachycardia, hallucinations, seizures, coma

• 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

6. Large-Conductance Calcium-Activated Potassium Channel Openers

• 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.

___________end of transcription____________

The only way of finding the limits of the possible is by going beyond them into the impossible.