6A. Pharmacology of Respiratory Drugs (URTIs) Flashcards
Pathophysiology of the upper respiratory tract
URT includes nose, sinus, pharynx & larynx:
- Nasal cavity is connected to 4 sinuses
- Purpose of sinuses is to warm & moisten the inspired air
- Tonsils are 1st line of defence against pathogens - trapped & expelled
- Goblet cells produce mucus
Inflammatory response in the upper respiratory tract
- When pathogens enter a cell, they multiply & spread to surrounding tissue, thus creating an inflammatory response
- Mucus traps pathogens & eventually expels them out
- Fever occurs to reduce pathogen production
URTI types, causes & infections (3)
- Rhinitis - Infection in the nose/nasal cavity
- Viruses e.g. rhinovirus, influenza, respiratory syncytial virus can cause symptoms such as rhinorrhea (runny nose)
- Bacteria e.g. S. pneumoniae can causes symptoms of rhinosinusitis (inflammation of the nasal cavity & paranasal sinuses) - Pharyngitis - Infection of the pharynx/throat
- Causes symptom of sore throat - Laryngitis - Infection of the larynx
- Causes symptoms of hoarse voice & cough
All are accompanied with fever, loss of appetite & fatigue
Treatments for viral URTIs
Rest
Fluids
Analgesia:
- Paracetamol
- Ibuprofen
Nasal decongestants:
- Xylometazoline/oxymetazoline
- Phenylephrine, pseudoephedrine
Cough mixtures:
- Expectorants e.g. guaifenesin
- Suppressants e.g. pholcodine, codeine
Antihistamines
Nasal decongestants
Alpha2 receptors on precapillary arterioles induce constriction of smooth muscle of vessel through calcium ions
- Vasoconstriction reduces blood flow into capillary bed, which reduces excess EC fluid associated with congestion
Alpha1 receptors populate post capillary venues, which accomodate large volumes of blood
- Stimulation results in vasoconstriction
By constricting blood vessels, decongestants decrease oedema & rhinorrhoea
Alpha1-stimulation activation
- Alpha1 stimulation results in vasoconstriction through the mobilisation of calcium & phosphorylation of key enzymes
- Result is reduction of volume of blood in the mucosa & mucosal volume leading to reduced nasal congestion
- Decongestants are sympathomimetics & act directly (described above) or indirectly
Structure activity relationships
Sympathomimetics (indirect acting) displace noradrenaline from storage vesicles or by directly binding to the adrenergic receptor
In Ephedrine the methyl group on the -carbon prevents it from being oxidised by MAO
Side effects of decongestants - Topical (nasal sprays / drops)
Rebound congestion (chemical rhinitis/hyperemia) is common
- Possibly due to repeated contraction of vasculature causing ischaemia & mucosal damage
- May apply more to alpha2 agonists
- Receptor desensitisation or down regulation of receptors
Acts rapidly (within minutes) With therapeutic doses, there are no systemic side effects
Side effects of decongestants - Systemic (oral)
- Hypertension & reflex bradycardia due to generalised vasoconstriction
- CNS stimulation especially with lipid soluble
- Increased heart rate - indirect / mixed acting
- Urinary retention in patients with partial obstruction e.g. prostate hypertropy
- Mydriasis potentially blocking drainage of aqueous humor (contraindicated in glaucoma)
- Affect metabolic function (caution in thyroid disease, diabetes & endocrine disorders)
Cough
- Defensive mechanism
- Generally beneficial but also symptom of serious conditions such as asthma, COPD & lung cancer
- Also symptom of extra-pulmonary conditions e.g. post-nasal drip, GORD, ear/heart disorder
- Could be side effects of medications e.g. ACE-inhibitors
- Common link is activation of subsets of airway sensory nerves
- Cough suppressants (antitussives) act centrally (opioids) or peripherally
Centrally acting antitussives - codeine, morphine, pholcodine, dihydrocodone
- All have action on the µ opioid receptor
- At effective doses can cause nausea, addiction, respiratory depression
- Codeine prescription only & should be avoided in CYP2D6 ultra-rapid metaboliser & under 12 years of age
Centrally acting antitussives - dextrmethorphan
- D dimer of codeine analogue, levorphanol
- Act on sigma receptors centrally & peripherally
- Most commonly combined with guaifenesin (expectorant)
- Side effects include dizziness, drowsiness, nausea, GI upset
- When used with SSRIs or TCAs can result in serotonergic syndrome
- Care when used with CNS depressants (alcohol, narcotics, tranquillisers)
Mucous properties
- Elasticity & viscosity critical properties of mucous (non-newtonian fluid)
- Coughing has direct relationship with viscosity & indirect with elasticity - therefore for mucosal clearance requires thick mucous, low elasticity & high viscosity
- Ciliary force direct relationship with elasticity & indirect with viscosity - therefore for mucosal clearance require a thin mucous layer, high elasticity & low viscosity
For clearance dependent on where the mucus is:
- Main airways (cough)
- Distal airways (mucous clearance enhancer)
Properties of cough products
- Expectorants - increase secretion or mucous hydration e.g. hypertonic saline
- Mucolytics - reduce viscosity by dissociating disulphide bonds e.g. N-aceyl cysteine
- Mucokinetics - increase transportability of mucous by coughing e.g. salbutamol
- Mucoregulators - reduce mucous hyper secretion
Expectorant / Mucolytic - Guaifenesin
- Reduces the surface tension & viscosity of the mucous, increasing the ease of expectoration
- Mucous removal is facilitated by increased flow of the thinned secretions via ciliary action
- Studies on efficacy have failed to show either improved pulmonary function or decreased sputum viscosity
- Use with caution in porphyria (possibly porphyrogenic) & history of asthma
- Cough mixtures should not be used in children
