Pharmacological Treatment of Cough, Cold, & Flu

Man B Paudyal

Common Cold Facts• On average, people have 3-12 colds per

year• The common cold and related conditions

annually result in:– 250 million restricted activity days– 30 million lost work or school days– one of the most expensive illnesses in the U.S.

• More prevalent in children

Common Cold Etiology• Viruses

– rhinoviruses (40-50% of cases)– influenza viruses– parainfluenza viruses– respiratory syncytial viruses– coronaviruses– adenoviruses– coxsackieviruses– enteric cytopathic human orphan (ECHO) viruses

Transmission of the Common Cold

• Direct virus spread– touching infected object (inoculum of virus)– self-inoculation (touching own mucous

membranes- eyes or nose, etc.)– commonly transmitted by children

• Indirect droplet spread– sneezing and coughing– secondary method of transmission

What this means!!!

• Most colds are transmitted via hand to mucosal tissue contact.

• ….Cause is directly related to lack of washing hands!!!

Clinical Presentation: Common Cold

• Sore or scratchy throat• Sneezing• Rhinorrhea (clear or purulent)• Nasal congestion• Fever may occur in children• Adults may experience malaise• Non-productive cough that may become

productive as the cold progresses

Common Cold

• Median duration of symptoms– 7-13 days

• Seasonal variation– peak occurrence:

• September (back to school surge)• October• early spring

Clinical Presentation: Influenza• Headache, sore throat, cough, runny nose, and

sneezing• Non-productive cough• Disabling impact• Sudden fever, sweating, and chills• Malaise and mylagia

– may last up to 2 weeks • Backache• Sensitivity to light

Common Cold and InfluenzaSymptom Common

ColdInfluenza

Fever Rare Sudden OnsetTemp 102-104 F

Headache Rare ProminentMyalgia Slight ProminentFatigue Mild ExtremeRhinitis Common Less CommonCongestion Common Less CommonSneezing Common Less CommonSore Throat Common Less CommonCough Mild, Hacking Common, Often SevereComplications Sinusitis Bronchitis, Pneumonia

Common Cold Prevention and Treatment

• Prevention:– patient education– hand washing

• Treatment goal:– relieve symptoms– minimize adverse effects– improve patient quality of life

Natural Products

Zinc• Mechanism of action is unknown.

– Hypothesized to inhibit viral shedding but unproven.

• Clinical studies are limited and controversial.• Lozenges generally have 23 mg Zn and should be

taken q2h while awake!• Adverse effects are not uncommon but are not

life-threatening.Adverse Effect Incidence(%)

Nausea 20.4Mouth Irritation 24.5

Bad Taste 79.6

Dry mouth 10.2

Vitamin C

• Anecdotal evidence only!• Correlational data suggest vitamin C may

participate in immune function– Enhance WBC function and activity– Increases interferon levels– Improves antibody levels and responses– Increases secretion of thymic hormones

Echinacea

• Chemical analysis has revealed numerous constituents with pharmacological activity.

• Appears to be most effective in patients with compromised immune systems.

“Cough Medicine”

Expectorants and Cough Suppressants

Expectorants

• Irritation of the bronchioles produces an increase in mucoprotein content and a concomitant increase in mucus viscosity.

• Most expectorants act by reducing the surface tension of secretions.

• Remember the adage, water is good for what ails you?– Water is indeed the best expectorant available

Expectorants (continued)

• Other expectorants include guiafenesin, although efficacy is not proven.

• Herbal remedies used as expectorants include licorice, horehound, thyme, and eucalyptus.– The last three act by stimulating bronchial

glands.

Cough Suppresants/Antitussives

• First question should be, “Do we want to suppress this cough?!?”

• Antitussives act at one of two sites– Centrally on the medullary cough center– Locally at the site of irritation

• Local actions– Increase formation and secretion of saliva which produces

more frequent swallowing, thereby diminishing the cough reflex

– Some have local anesthetic properties on the lung and throat, which suppresses the cough

Dextromethorphan• Antitussive

– d-isomer of a codeine analog– central acting agent– low addiction potential– no analgesic properties

• Some drug interactions• May not work as well as opiates

Codeine• Use

– narcotic analgesic – anti-tussive-direct central action in the medulla

• High abuse potential– Schedule V

• Consider drug interactions– CNS depressant

Codeine• Adverse Effects:

– >10%: • Drowsiness, Constipation

– 1-10: • CNS: dizziness, confusion, euphoria, malaise, headache,

restlessness, CNS stimulation• Respiratory: SOB, dyspnea (use with caution in patients with

respiratory disorders)• Skin: rash, urticaria• GI: xerostomia, anorexia, N/V• GU: decreased urination, ureteral spasm

Lozenges

• Lozenges or compressed tablets:– 5-10 mg menthol

• MOA:– local anesthetic effect on nerve receptors with the

respiratory tract

• Directions:– 2 YOA and older: Place one lozenge in the mouth and

allow to dissolve slowly over several minutes Q1H PRN or AD

Camphor and Menthol

• Found in Vicks VapoRub and MenthoRub

– Rubbed on throat and/or chest or used in humidifiers

• Menthol is also found in some cough syrups• Both menthol and camphor have local

anesthetic properties on the throat and lungs

Combination Preparations

• Many cough medicines (syrup, capsule, or tablet) contain compounds for relief of other symptoms.– Decongestants (esp pseudoephrine & PPA)– Antihistamines

• Promethazine acts as antihistamine and as local anesthetic in throat thereby suppressing cough

Decongestants• Mechanism of action:

– Activate and -adrenergic receptors.

• Effect as decongestant:– directly stimulate alpha-adrenergic receptors of respiratory mucosa

causing vasoconstriction– shrinks swollen mucosa and improves ventilation– directly stimulates beta-adrenergic receptors causing bronchial relaxation

• Other effects (adverse effects)– Vasoconstriction– Tachycardia– Increase glycogenolysis and gluconeogenesis– CNS stimulation Can result in angina, HTN, and

worsening of CV disease

Topical Decongestants• Available in nasal drops or sprays• Local action

– minimizes systemic absorption• Available OTC• Side Effects:

– rhinitis medicamentosa (rebound vasodilation)– burning, stinging, sneezing, nasal dryness

• Limit use to 3-5 days

Nasal Saline or Drops• MOA:

– soothes irritated nasal tissues– moisturizes nasal mucosa

• Dosage Forms:– commercial: sprays, drops– homemade solution: 1 tsp. salt / 7 oz. warm water

• Dosage:– 2-6 drops per nostril QID PRN nasal dryness or

discomfort

Topical Decongestants

Topical Agent: Duration of Action:

Phenylephrine HCl Up to 4 hoursNaphazoline HCl 4-6 hoursTetrahydralazine HCl 4-6 hoursOxymetazoline HCl Up to 12 hoursXylometazoline HCl Up to 12 hours

Systemic Decongestants

• Include– Pseudoephedrine

• duration is 4-6 hours

– Phenylpropanolamine (PPA)• duration is 4-6 hours

– Some natural products contain Ephedra (epinephrine)• duration is 6-8 hours

• Effects on blood pressure, heart rate– PPA>Ephedrine>Pseudoephedrine

Systemic Decongestants• Compared to topical decongestants:

– longer onset of action (no immediate relief)– longer duration of effect– no rebound vasodilation – no local irritation

• Risks:– increases heart rate, contractility– can significantly increase BP– can worsen angina

Systemic Decongestants• Overview of Side Effects:

– >10%• CV: tachycardia, palpitations, arrhythmias• CNS: nervousness, transient stimulation, insomnia, excitability,

dizziness, drowsiness• neuromuscular: tremor

– 1-10%• CNS: HA• GI: xerostomia, nausea• other: weakness, diaphoresis

– <1%• respiratory: SOB, dyspnea

Antihistamines

Histamine Receptor Subtypes

Receptor Subtype Distribution Postreceptor

MechanismH1 Smooth muscle,

endothelium, brain IP3, DAG

H2 Gastric mucosa, cardiac muscle, mast cells, brain

cAMP

H3 Pre-synaptic Inhibit histamine release

Histamine• Found in almost all tissues of the body

– Stored in mast cells

• Actions– Potent vasodilator of arterioles– Increases microvascular permeability– Bronchoconstriction– Contraction of GI smooth muscle– Increase gastric secretion

• Triple response (AKA “wheal and flare”– Immediate development of red spot around injection site due to microvascular

dilation.– Larger reddened area due to axon-mediated vasodilatory reflex response.– Appearance of a wheal due to increased capillary permeability.

Antihistamines

• Alkylamines• Ethanolamines• Ethylenediamines• Phenothiazines• Piperidines• Piperazines• Second Generation Agents

Mechanism of Action• Bind to and inhibit histamine-induced activation of H1 receptors• Some agents appear to block the release of inflammatory mediators

from mast cells and basophils (H2 action)– azatadine, terfenadine, cetirizine, and loratadine

• Antagonize histamine actions capillary permeability– “triple response”– itching– nasal, salivary, and lacrimal hypersecretion

• Some are known to bind and inhibit muscarinic, alpha, and serotonergic receptors

• Block sodium channels in excitable membranes– provide local anesthesia similar to lidocaine– diphenhydramine and promethazine are very potent

H1 Receptor Antagonists• Side effects

– Sedation• Antimuscarinic effect: must cross BBB

– Anticholinergic side effects (esp. ethanolamine & ethylenediamine subgroups)

• dry mouth, urine retention, constipation– GI side effects

• anorexia, nausea, vomiting, epigastric pain• some decrease N&V and motion sickness

– Orthostatic hypotension (esp. phenothiazine subgroup)• binds to and inhibit alpha receptors

• Drug interactions– cardiac drugs, CNS depressants, antibiotics

H-1 vs Ach Antagonism• Pharmacophore H-1

• Pharmacophore Ach

• Bulky Groups Aromatic and Cycloalkyl

• Amine=Tertiary

• Bulky Groups Aromatic

• Amine Tertiary or Quarternary

Bulky

Bulky

H-Bond

ChainC Amine

Bulky

Bulky

ChainC Amine

H1 Receptor Antagonists- Role in Therapy

• First line treatment– perennial and seasonal allergic rhinitis

• Symptom control– allergic rhinitis– allergic conjunctivitis

• Contraindications– BPH, bladder neck obstruction– narrow-angle glaucoma– acute asthma attacks– stenosing peptic ulcer, pyloroduodenal obstruction– neonates and newborn infants

H1 Receptor Antagonist Selection

• Side Effects– sedation– anticholinergic side effects– GI side effects

• Duration of action– dosing schedule– compliance

• Risk of drug interactions• Costs• Other patient characteristics

Controlling Sedation with the H1 Antagonists

• Slow dose titration– institute therapy using slow dosage titration

• SR dosage forms– administer evening doses of long acting (QD) products or

sustained release dosage forms of shorter acting products

• Second generation– select a second generation relatively non-sedating product

• Add a decongestant– increased CNS stimulation often offsets sedation

• Chronic administration

H1 Receptor Antagonist Titration Schedule

Start with a small dose QHS only and continue this dose for at least 3 days or until the patient has minimal AM sedation

Add a small dose in the morning and continue this regimen for another 3 days

Continue increasing the dose in this manner, adding to the HS dose alternately with the AM dose, until symptom control is achieved

Do not D/C medication once symptoms improve; It is important to maintain the routine in order to avoid symptoms and sedation

First Generation Agents

“Sedating”

First Generation H1 Antagonists• General Class Side Effects:

– >10%• CNS: mild to moderate sedation• Respiratory: thickening of bronchial secretions

– 1-10%• CNS: HA, fatigue, nervousness, dizziness• GI: appetite, weight gain, nausea, diarrhea, GI pain, xerostomia• neuromuscular: arthralgia, weakness• respiratory: pharyngitis

– <1%• hepatic: hepatitis• respiratory: bronchospasm

First GenerationAntihistamine Comparison

Drug Sedation AnticholActivity

GI

Alkylamine Class 1 ++ +++ -Ethanolamine Class 2 ++++ ++++ +Ethylenediamine Class 3 +++ + +++Phenothiazine Class 4 ++++ ++++ -Piperazine Class +++ ++ -Piperidine Class +++ +++ -

1 Brompheniramine least sedating of class2 Diphenhydramine most sedating of class3 Pyrilamine least sedating of class4 Promethazine most sedating of class

Alkylamines“-pheneramines”

Anti-histamine

Dosing Interval

Anti-ACh Activiy

Anti-H1 Acticity

Sedation

Brom-4-6 +++ ++++ +

Chlor- 4-6 +++ +++ +

Dexchlor- 4-6 +++ ++++ +

Tripolodine ++ ++ ++

Ethanolamines

Anti-histamine D.I. (hr)

Anti-ACh Activiy

Anti-H1 Acticity

Anti-5HT Activity

Na+ Channel Blockade

Sedation

Carboxyamine 6-12 ++++ ++ -/+ -/+ ++

Clemastine 12 ++++ ++ + - +++

Diphenhydramine 6-8 ++++ ++ + +++ ++++

Dimehydrinate 4-8 +++ + ++ -/+ ++++

Doxylamine 1 +++ + ++ - ++++

Ethylenediamines

Anti-histamine D.I. (hr)

Anti-ACh Activiy

Anti-H1 Acticity

Sedation

Pyrilamine 6-8 -/+ + +

Tripelennamine 4-6 -/+ ++ ++

Phenothiazines• Several class indications:

– antihistamine– antiemetic, motion sickness– sedation– neuroleptic

• Antihistamine:– block H1 receptors

• Antiemetic:– blocks postsynaptic mesolimbic DA receptors– partially blocks CTZ center– blocks acetylcholine receptors in the vestibular center

Phenothiazines

• Antiemetic (continued)– halogenation of the R1 side chain of the

phenothiazines • increases antiemetic activity and frequency of EPS side

effects • decreases sedation and hypotension

– thiethylperazine (Torecan®) – prochlorperazine (Compazine ®)

• Other– alpha blockade

• orthostatic hypotension

Phenothiazines• Caution in elderly (> 60 YOA):

– most likely to develop side effects• hypotension, syncope, confusion, EPS side effects,

agranulocytosis, photosensitivity, akathisia, and dystonia during phenothiazine therapy

– increased risk with prolonged therapy

Piperidines

Anti-histamine D.I. (hr)

Anti-ACh Activiy

Anti-H1 Acticity

Anti-5HT Activity

Sedation

Azatidine 12 ++ ++ + ++

Cyproheptadine 8 ++ ++ ++ +

Phenindamine 4-6 ++ ++ + +/-

Piperazines

Anti-histamine D.I. (hr)

Anti-ACh Activiy

Anti-H1 Acticity

Sedation

Cyclizine 4-6 ++ ++ +

Dimenhydrinate 4-6 +++ ++ ++++

Hydoxyzine 6-8 ++ +++ ++++

Meclizine 24 ++ ++ +

Second Generation AgentsPeripherally Selective

Non-Sedating

Second Generation Agents- Relatively Non-Sedating

• Less lipophilic– decreased distribution across BBB into CNS– decreased centrally mediated sedation

• Drug interactions– do not interact with ethanol or CNS

depressants to intensify sedation or inebriation

Patient Selection for Second Generation Agents

• Expensive• H1 treatment failure

– poor response– non-compliance– significant side effects

• Evaluate– drug interactions

Second Generation Antihistamine Comparison

Drug Sedation AnticholActivity

GI

Terfenadine + + -Astemizole + + +Cetirizine + + +Fexofenadine + +

Loratadine + + +

Terfenadine and Astemizole removed from market

Azelastine• “Third” generation antihistamine• Products:

– Astelin®

• Mechanism of Action– antagonizes histamine at H1 receptors– may also have anti-inflammatory activity

Azelastine• Pharmacokinetics

– 40% of dose reaches systemic circulation– metabolized in liver by CyP450– active metabolite

• Adverse Effects– 5-12% somnolence– 9-32% bitter taste– nasal burning, epistaxis, sore throat, dry mouth

• Contraindicated in pregnancy