Respiratory drugs and analgesics

Question 1

NSAIDs cellular pharmacodynamics

Answer 1

Irreversible, non-selectively inhibits COX enzymes preventing production of prostanoids.

Question 2

Systemic pharmacodynamics of NSAIDs

Answer 2

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.

Question 3

Aspirin analgesic dose

Answer 3

300-900mg every 4 hours.

Question 4

Contraindications of NSAIDs

Answer 4

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.

Question 5

Adverse drug reactions of NSAIDs

Answer 5

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

Question 6

Selective COX-2 Inhibitor indications

Answer 6

Long term pain relief (arthritis, dysmenorrhea)

Question 7

NSAID and COX-2 inhibitor comparison

Answer 7

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.

Question 8

Cellular pharmacodynamics of COX-2 Inhibitors

Answer 8

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).

Question 9

Contraindications to COX-2

Answer 9

Any CVD hisory.

Question 10

Adverse drug reactions of COX-2 Inhibitors

Answer 10

Cardiovascular events: due to inhibitionof COX2 - this is predominantly responsible for producing PGI2 which normally inhibits platelet aggregation.

Question 11

Decongestants indications

Answer 11

Acute and chronic rhinitis

Question 12

Decongestants cellular pharmacodynamics

Answer 12

Sympathomimetic amines. Agonise alpha adrenoreceptors on smooth muscle in the respiratory tract, producing vasoconstriction of dilated nasal vessels.

Question 13

Decongestants systemic pharmacodynamics

Answer 13

Reduces tissue hyperaemia, oedema and nasal congestion.

Question 14

Contraindications to decongestants

Answer 14

HTN, coronary artery disease (arrhythmias)

Question 15

Adverse drug reactions of decongestants

Answer 15

Hypertension, tachycardia, palpitations, CNS stimulation, insomnia, tremor etc

Question 16

Antitussives indications

Answer 16

Dru cough - opioid dervicatives

Productive cough - expectorants, demulcents, muclytics.

*Investigate underlying disorder as coughing is usually desirable! Stop smoking. *

Question 17

Cellular pharmacdynamics dry cough antitussives

Answer 17

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.

Question 18

Expectorant antitussive cellular pharmacodynamics

Answer 18

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,

Question 19

Demulcents cellular pharmacodynamics

Answer 19

For productive cough.

Thought to suppress coughs by forming a protective layer over sensory receptors in the pharynx.

Question 20

Mucolytics cellular pharmacodynamics

Answer 20

Acetylcysteine reduces mucus viscosity by splitting disulfide bonds in mucoproteins, bromhexine thought to improve mucous flow by enhancing hydrolysing activity of lysosomal enzymes.

Question 21

Systemic pharmacodynamics antitussives

Answer 21

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

Question 22

Antitussive contraindications

Answer 22

Opioids in respiratory failure, asthma and COPD and children <2 years.

Question 23

Adverse drug reactions antitussives

Answer 23

Opioids may cause opioid dependence, lethargy, stupor etc.

Expectorants and mucolytics may cause nausea, vomiting and abdominal pain.

Question 24

Histamine antagonsists indications

Answer 24

Allergic rhinitis, chronic urticaria

Question 25

Histamine antagonists cellular pharmacodynamics

Answer 25

**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

Question 26

Systemic pharmacodynamics of histamine antagonists

Answer 26

Suppress symptoms of allergies such as runny nose and watery eyes.

Question 27

Histamine antagonists contraindications

Answer 27

Children \<2 years

Question 28

Adverse drug reactions to histamine antagonists

Answer 28

Drowsiness, fatigue (ever newer drugs to some extent)

Question 29

Inhaled beta angonists indications

Answer 29

Acute asthma, COPD. 'Relievers' and 'Symptom controllers'

Question 30

Inhaled beta agonist comparison

Answer 30

**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.

Question 31

Cellular pharmacodynamics of inhaled beta blockers

Answer 31

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.

Question 32

Systemic pharmacodynamics of inhaled beta agonists

Answer 32

Relaxes bronchial smooth muscle, increasing FEV1 reducing residual volume and delaying onset of dynamic hyperinflation during exercise.

Question 33

Pharmacokinetics of inhaled beta agonists

Answer 33

Long acting beta agonists (LABA) have been engineered to have longer duration of effect. ## Footnote **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.

Question 34

Adverse drug reaction inhaled beta agonists

Answer 34

Tremor, tachycardiam cardiac dysrhythmias (due to systemic absorption)

Question 35

Muscarinic antagonists indications

Answer 35

COPD, acute asthma. Alternative 'reliever' and 'symptom controller'

Question 36

Muscurinic antagonist comparison

Answer 36

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.

Question 37

Cellular pharmacodynamics of muscarinic antagonists

Answer 37

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.

Question 38

Systemic pharmacodynamics of muscarinic antagonists

Answer 38

Attenuating vagal tone reduces bronchospasm and mucous production, increasing exercise tolerance.

Question 39

Adverse drug reactions of muscarinic antagonists

Answer 39

Dry mouth, cough, throat irritation, urinary retention, glaucoma. Quite safe due to poor circulatory absorption (not lipid soluble).

Question 40

Glucocorticoids indications (resp)

Answer 40

Asthma, COPD

Question 41

Cellular pharmacodynamics of glucocorticoids

Answer 41

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.

Question 42

Systemic pharmacodynamics glucocorticoids

Answer 42

Inhibits both early and late phases of inflammation: initial redness, heat, pain and swelling: and later wound healing, repair and proliferation.

Question 43

Dosing of glucocorticoids

Answer 43

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.

Question 44

Adverse drug effects of glucocorticoids

Answer 44

Oral thrush, sore throad, croaky voice, adrenal suppression (bone density, glaucoma, cataract, skin thinning, bruising, impaired growth, pschosis, fat redistrubition).

Question 45

Bronchodilators indications

Answer 45

Asthma, COPD

Question 46

Bronchodilators comparisons

Answer 46

**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.

Question 47

Cellular pharmacodynamics of bronchodilators

Answer 47

**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.

Question 48

Systemic pharmacodynamics of bronchodilators

Answer 48

Bronchodilation, some inflammatory modulation.

Question 49

Adverse drug reactions to bronchodilators

Answer 49

Xanthine: insomnia, nervousness, nausea, headache - common. Seizure, arrhythmias.