Respiratory drugs and analgesics Flashcards
NSAIDs cellular pharmacodynamics
Irreversible, non-selectively inhibits COX enzymes preventing production of prostanoids.
Systemic pharmacodynamics of NSAIDs
Anti-inflammatory
Due to decrease in PGE2 and prostacyclin causing reduced vasodilation and oedema.
Analgesic
Due to decrease prostaglandin production and thus less sensitisation of nociceptive nerve endings to inflammatory mediators such as bradykinin.
Antipyretic as NSAIDs prevent IL-1 activating COXs in the CNS which produce prostaglandins which raise the hypothalamic set point.
Aspirin analgesic dose
300-900mg every 4 hours.
Contraindications of NSAIDs
Beware ‘tripply whammy’ combination of ACEI/ARB + diuretic + NSAID causing acute renal failure.
Aspirin
Children <12 years due to risk of Reye’ssyndrome when taen during a viral illness.
Adverse drug reactions of NSAIDs
GI bleeding: due to inhibition of COX1 which normally provides prostaglandins to maintain themucosal lining of the stomach.
Ibuprofen is ‘gentlest’ on the stomach.
Cardiovascular events
Selective COX-2 Inhibitor indications
Long term pain relief (arthritis, dysmenorrhea)
NSAID and COX-2 inhibitor comparison
While COX-2 theoretically cause fewer GI side effects than non-selective NSAIDs, CLASS trial showed no real difference.
*Rofecoxib *did show fewer GI side effects, but 5x more MI.
Cellular pharmacodynamics of COX-2 Inhibitors
Selectively inhibits COX-2 enzymes avoiding adverse effects. COX-2 is thought to be responsible for the most inflammation, pain and fever; wile adverse effects are throught to be mosty due to inhibition of COX-1 (housekeepning enzymes).
Contraindications to COX-2
Any CVD hisory.
Adverse drug reactions of COX-2 Inhibitors
Cardiovascular events: due to inhibitionof COX2 - this is predominantly responsible for producing PGI2 which normally inhibits platelet aggregation.
Decongestants indications
Acute and chronic rhinitis
Decongestants cellular pharmacodynamics
Sympathomimetic amines. Agonise alpha adrenoreceptors on smooth muscle in the respiratory tract, producing vasoconstriction of dilated nasal vessels.
Decongestants systemic pharmacodynamics
Reduces tissue hyperaemia, oedema and nasal congestion.
Contraindications to decongestants
HTN, coronary artery disease (arrhythmias)
Adverse drug reactions of decongestants
Hypertension, tachycardia, palpitations, CNS stimulation, insomnia, tremor etc
Antitussives indications
Dru cough - opioid dervicatives
Productive cough - expectorants, demulcents, muclytics.
*Investigate underlying disorder as coughing is usually desirable! Stop smoking. *
Cellular pharmacdynamics dry cough antitussives
Activate neuronal G-protein coupled oiioid receptors, inhibit adenylate cyclase, reducing cAMP levels and activating K+ channels hyperpolarising neuron. This reduces release of substance P, which is a neurokinin binding NK-1 which activates the cough centre in the medulla.
Expectorant antitussive cellular pharmacodynamics
Thought to promote bronchial secretions, ciliary action and productive coughing by irritant action on mucosal membranes.
May also soothe by lubricating dry tissues.
Mainly placebo affect,
Demulcents cellular pharmacodynamics
For productive cough.
Thought to suppress coughs by forming a protective layer over sensory receptors in the pharynx.
Mucolytics cellular pharmacodynamics
Acetylcysteine reduces mucus viscosity by splitting disulfide bonds in mucoproteins, bromhexine thought to improve mucous flow by enhancing hydrolysing activity of lysosomal enzymes.
Systemic pharmacodynamics antitussives
Opioid derivates reduce frequency of dry, irritating cough.
Expectorants increase mucous production and movement
Demulcents suppress coughing
Mucolytics reduce mucus viscosity and aid its digestion
Antitussive contraindications
Opioids in respiratory failure, asthma and COPD and children <2 years.
Adverse drug reactions antitussives
Opioids may cause opioid dependence, lethargy, stupor etc.
Expectorants and mucolytics may cause nausea, vomiting and abdominal pain.
Histamine antagonsists indications
Allergic rhinitis, chronic urticaria
Histamine antagonists cellular pharmacodynamics
Cellular: selectively antagonise the action of histamine at H1 receptors in both CNS and periphery. Histamine released from mast cells and basophils causes local inflammation, smooth muscle contraction and blood vessel dilation. Older ‘drowsy’ drugs penetrate blood brain barrier well and so cause CNS sedation, cognitive impairment and motor retardation. Newer, less sedating drugs do not penetrate the blood brain barrier well
Systemic pharmacodynamics of histamine antagonists
Suppress symptoms of allergies such as runny nose and watery eyes.
Histamine antagonists contraindications
Children <2 years
Adverse drug reactions to histamine antagonists
Drowsiness, fatigue (ever newer drugs to some extent)
Inhaled beta angonists indications
Acute asthma, COPD.
‘Relievers’ and ‘Symptom controllers’
Inhaled beta agonist comparison
Asthma
SABAs are first line treatment in acute asthma. If needed >2 times a week, preventative treatment should be used.
Step 2 is an ICS
Step 3 is ICS + LABA
Step 4 is other symptom controllers
In acute exacerbations, an oral corticosteroid may be used.
Cellular pharmacodynamics of inhaled beta blockers
Agonise B2 receptors of bronchial smooth muscle, upregulating PKA (via cAMP and adenylate cyclase) which inhibits MLCK and thus prevents phosphorylation and contraction of smooth muscle. Also inhibits mediator release from mast cells and macrophages, and increase ciliary mucous clearance.
Systemic pharmacodynamics of inhaled beta agonists
Relaxes bronchial smooth muscle, increasing FEV1 reducing residual volume and delaying onset of dynamic hyperinflation during exercise.
Pharmacokinetics of inhaled beta agonists
Long acting beta agonists (LABA) have been engineered to have longer duration of effect.
SABAs are administered as needed and have a mximum effect in 30 mins, and a duration of 3-5 hours.
LABAs are used once daily and have a prolonged duration of effect (8-12 hours), often combined with corticosteroid in one inhaler.
Adverse drug reaction inhaled beta agonists
Tremor, tachycardiam cardiac dysrhythmias (due to systemic absorption)
Muscarinic antagonists indications
COPD, acute asthma.
Alternative ‘reliever’ and ‘symptom controller’
Muscurinic antagonist comparison
COPD tends to respond better to muscarinic antagonists that does asthma (as M3 receptors are mostly in the large airways while asthma affects small airways).
COPD treatment: SABA/ipratopium intermittent, LABA/tiotropium for maintenance, theophylline, inhaled corticosteroids (if responsive), O2.
Cellular pharmacodynamics of muscarinic antagonists
Anticholinergic - non-discriminatory muscarinic antagonists which competitively inhibit M3 receptors. In smooth muscle cells prevent production of IP3 and DAG, reducing [CA2+] and inhibiting contraction. In glandular and mast cells, decreases cGMP and IP3 reducing mucous secretion and release of mediators.
Systemic pharmacodynamics of muscarinic antagonists
Attenuating vagal tone reduces bronchospasm and mucous production, increasing exercise tolerance.
Adverse drug reactions of muscarinic antagonists
Dry mouth, cough, throat irritation, urinary retention, glaucoma. Quite safe due to poor circulatory absorption (not lipid soluble).
Glucocorticoids indications (resp)
Asthma, COPD
Cellular pharmacodynamics of glucocorticoids
Steroids cross nuclear membrane and bind to transcription factors. Inhibit production of vasodilators by inhibiting COX-2. By inducing annexin -1 (lipocortin-1) they inhibit production of leukotrienes and other inflammatory mediators. Inhibits IL-5 which activates eosinophils and IL-3 which activates mast cells. Also decrease neutrophil, macrophage movement, decrease TH2 cell action, impair fibroblast function and atrophy thymus gland.
Systemic pharmacodynamics glucocorticoids
Inhibits both early and late phases of inflammation: initial redness, heat, pain and swelling: and later wound healing, repair and proliferation.
Dosing of glucocorticoids
Steroids are inhaled to reduce systemic delivery and minimise side-effects.
Rinse mouth after use.
‘Rescue course’ of oral prednisolone may be needed in exacerbations, although ensure short course due to side effects.
Adverse drug effects of glucocorticoids
Oral thrush, sore throad, croaky voice, adrenal suppression (bone density, glaucoma, cataract, skin thinning, bruising, impaired growth, pschosis, fat redistrubition).
Bronchodilators indications
Asthma, COPD
Bronchodilators comparisons
**Leukotriene-receptor antagonists **superior additive to LABA in preventing exercise induced asthma, limited evidence in COPD. Expensive so used last line for steroid sparing effect.
Xanthines used in addition to steroids in: COPD and asthma unresponsive to beta agonists, and IV in acute asthma.
Chloride channel blockers now rarely used, but effective against antigen, exercise and irritant induced asthma.
Cellular pharmacodynamics of bronchodilators
Chloride channel blockers prevent histamine release form mast cells by blocking calcium channels. They also supress activation of sensory nerves, de-sensitise neuronal reflexes and inhibit release of T-cell cytokines.
Leukotriene-receptor antagonists block binding of leukotrienes to the cysteinyl leukotriene receptor CysLT1 (found in respirtaory mucosa and inflammatory cells) preventing bronchospasm and inflammation.
**Xanthines **action in unclear: ibhibiting phsophodiesterase may be responsible for smooth muscle dilation and some anti-inflammatory effect; antagonising adenosine may be responsible for side-effects; and activating histone deaetylase (HDAC) may reverse resistance to anti-inflammatory effect of corticosteroids.
Systemic pharmacodynamics of bronchodilators
Bronchodilation, some inflammatory modulation.
Adverse drug reactions to bronchodilators
Xanthine: insomnia, nervousness, nausea, headache - common. Seizure, arrhythmias.
