Lecture 11: Over The Counter Medication (Cough and Cold)

Question 1

What are the characteristics of the cough and cold medicine in the pharmacy?

Answer 1

despite the plethora of products, there are only a limited number of active ingredients approved for treatment of cold and flue symptoms (and available over-the-counter)

marketing of different products usually a reflection of dose (“severe”, “maximum strength”, “Children’s”), formulation (“liquid gels”), or simply emotion (“multi action”)

there are also a number of “Natural” or homeopathic remedies that are sold alongside “traditional” medicine

Question 2

What symptoms do cough and cold medications treat?

Answer 2

commonly available over-the-counter cough and cold medications contain either singly or in combination a decongestant, cough suppressant, expectorant and/or antipyretic/analgesic

used to treat symptoms of upper respiratory infections (runny nose, congestion, cough and fever)

Question 3

What is the cough reflex?

Answer 3

coughing is a reflex to clear the breathing passage of irritants, microbes, fluids, and mucus

it is a common symptom of upper respiratory tract viral infections

however, there are other causes of cough (e.g., bacterial infection) where suppression of cough may be inappropriate

important to identify the cause before treating the cough (and should treat the underlying cause)

Question 4

What is the neural component of the cough reflex?

Answer 4

the coughing reflex is initiated by stimulation of sensory nerves innervating the throat and lungs

sensory neurons contain several receptors that detect irritants and inflammation (e.g., P2X3, TRPV1)

sensory neurons send this information to the nucleus tractus solitarus (nTS) in the brainstem medulla oblongata

efferent neurons via parasympathetic and motor nerves stimulate the diaphragm, intercostal muscles and lung to initiate a “noisy expiration” (i.e. cough)

Question 5

What are antitussives?

Answer 5

OTC drug that inhibit the cough reflex (“antitussives”) do so mostly by inhibiting neurons in the nucleus tractus solitarus

despite the large number of OTC antitussive products on the market, there are only a few approved active ingredients (dextromethorphan, diphenhydramine, codeine)

many of these drugs are only moderately effective (at best!) at reducing cough in clinical trials

Question 6

What are the mechanisms involved in codeine antitussives?

Answer 6

codeine is a mu opioid receptor agonist

mu opioid receptors are located in the nucleus tractus solitarus as well as peripheral nerves innervating the respiratory tract

opioid receptors are inhibitory G-protein coupled receptors (Gi-GPCR)

Gi-coupled GPCRs inhibit adenylase cyclase activity and reduce neuronal activity

activation of opioid receptors inhibit of calcium channels, activate of K+ channels and inhibit of adenylate cyclase –> neuronal inactivation and reduced transmitter release

Question 7

What are the side effects of codeine antitussives?

Answer 7

opioid receptors are also located in brainstem regions that mediate breathing reflex (preBotzinger complex in the medulla oblongata)

high dose opioids inhibit breathing reflex and can lead to death (opioid overdose deaths)

not recommended for those under 18 (children more susceptible to respiratory depression)

low dose codeine (<8mg) is available OTC mixed with other ingredients like acetaminophen (e.g., Tylenol 1s)

due to the growing opioid overdose epidemic, Heath Canada was preparing to move codeine to prescription status, but based on public feedback, they have decided not to pursue this amendment

Question 8

What are the mechanisms involved in dextromethorphan antitussives?

Answer 8

dextromethorphan is a centrally active NMDA receptor antagonist

the NMDA receptor is a ligand gated ion channel gated by glutamate (excitatory)

like codeine, inhibits neurons in the nucleus tractus solitarus

despite being one of the most common OTC cough remedies, not all that effective at treating cough

Question 9

What are the mechanisms involved in diphenhydramine antitussives?

Answer 9

diphenhydramine is an antihistamine (H1 inverse agonist)

an inverse agonist is a drug that suppresses endogenous receptor signaling; an inverse agonist will behave as an antagonist in the presence of an agonist

H1 receptors are Gq coupled GPCRs, located on respiratory smooth muscles, stimulates sensory nerves producing coughing; diphenhydramine inhibits histamine action at these receptors

diphenhydramine also crosses the blood brain barrier to suppress neurons in the nucleus tractus solitarus

Question 10

How does honey work as an antitussive?

Answer 10

one of the most effective non-prescription treatments of cough is from the grocery store, not pharmacy

children’s cough assessed on first night (no treatment) and second night (with treatment)

cough improved from first night to second night, regardless of treatment

honey was significantly better than no treatment

dextromethorphan (DM) was not significantly better than no treatment

Question 11

What is the mechanism underlying congestion?

Answer 11

nasal congestion due to swelling (edema) of the nasal mucosa, and edema caused by vasodilation

sympathetic nervous system controls vascular tone

alpha 1 adrenergic receptors, alpha 2 adrenergic receptors, beta adrenergic receptors

Question 12

What are alpha 1 adrenergic receptors?

Answer 12

are located on vascular arterioles and activation leads to vasoconstriction

are Gq coupled GPCRs

Question 13

What are alpha 2 adrenergic receptors?

Answer 13

are located on vascular arterioles and veins, as well as broadly throughout the central and peripheral nervous system (e.g., side effects)

are Gi coupled receptors

Question 14

What are beta adrenergic receptors?

Answer 14

located on bronchioles (smooth muscle relaxation) and in the heart (increase cardiac output)

are Gs coupled GPCRs

Question 15

How do both alpha 1 receptors and alpha 2 receptors lead to smooth muscle contraction?

Answer 15

for alpha 1, activation of Gq proteins increase PLC and IP3 pathways; this stimulates release of calcium and smooth muscle contraction

for alpha 2, inhibition of adenylate cyclase reduces cAMP; cAMP is an inhibitor of myosin light chain kinase, an enzyme that phosphorylates myosin and cause contraction; inhibition of cAMP increases MLCK activation and increases smooth muscle contraction

Question 16

What are the mechanisms involved in pseudoephedrine decongestants?

Answer 16

is a non-specific agonist at the alpha and beta adrenergic receptors (sympathomimetic drug)

activates alpha adrenergic receptors in the mucosa of the respiratory tract leading to the vasoconstriction of blood vessels

activity at the beta adrenergic receptors causes smooth muscle relaxation leading to dilation of the bronchi and increased mucociliary clearance

shrinks swollen nasal mucous membranes, reduces tissue hyperemia, edema, and nasal congestion; increases nasal airway latency

Question 17

What are sympathomimetic drugs?

Answer 17

is a drug that produces effects similar to activation of the sympathetic nervous system

norepinephrine is the endogenous ligand (“neurotransmitter”) that activates adrenergic receptors

Question 18

What are some potential abuses associated with pseudoephedrine?

Answer 18

pseudoephedrine is structurally related to amphetamine and has stimulant properties (remember: there are adrenergic receptors throughout the peripheral and central nervous system)

potential abuse liability as can be used as a precursor for illicit methamphetamine production

for this reason, while technically OTC, sales are often controlled through the pharmacist

Question 19

What are the mechanisms involved in phenylephrine decongestants?

Answer 19

phenylephrine is a specific alpha1 adrenergic receptor agonist

like pseudoephedrine leads to vasoconstriction in the nasal mucosa, but does not lead to smooth muscle relaxation in the bronchi (nor impact heart rate)

cannot be chemically transformed into methamphetamine, so minimal abuse liability

but also, its less effective decongestant

Question 20

What are the mechanisms involved in oxymetazoline decongestants?

Answer 20

oxymetazoline is an alpha2 adrenergic agonist

applied directly to the nasal mucosa

more rapid onset of action and avoids side effects of systemically administered alpha2 adrenergic agonists (does not get to the brain)

rhinitis medicamentosa or “rebound congestion” is a risk with prolonged use; this is especially true for alpha2 agonists (less of a problem for alpha1 agonists)

Question 21

What are expectorants?

Answer 21

expectorants are oral drugs that enhance the clearance of mucus

back in the 1990s, there were lots of expectorants available, but lacked evidence for their efficacy so the FDA (and Health Canada) removed most of expectorants from the market

Guaifenesin (Mucinex) is the exception

Question 22

What are the mechanisms involved in guaifenesin expectorants?

Answer 22

bark from the Guaic tree (native to the Caribbean) was used by indigenous communities for its expectorant qualities

the active ingredient was purified and sold as guaifenesin

guaifenesin increases the output of bronchial secretions by decreasing the adhesiveness and surface tension (facilitates expulsion via the cough reflex)

mechanism of activation unknown, but may act as an irritant of gastric vagal receptors that recruit efferent parasympathetic reflexes causing glandular exocytosis that is comprised of a less viscous mucus mixture