S9: opioids & respiratory pharmacology

Question 1

Compare nociception and pain

Answer 1

Nociception – non conscious neural traffic due to trauma or potential trauma to tissue
Pain – complex, unpleasant awareness of sensation modified by experience, expectation, immediate context and culture

Question 2

Describe the pain pathway

Answer 2

Nociceptors stimulated
Release of substance P and glutamate
Afferent nerve stimulated
Fibres decussate 
Action potential ascends 
Synapse in thalamus
Project to post central gyrus

Question 3

List the different ways pain is modulated

Answer 3

Have modulators in peripheral system and in central system
Peripherally: substantia gelatinosa
Centrally: peri-aqueductal grey

Question 4

Outline how pain is modulated peripherally

Answer 4

Tissue damage stimulates A delta & C afferent nerves, which enter the dorsal horn (substantia gelatinosa (SG) is found here) and project to the thalamus, causing pain and sensation
Laminae 1+5 are where pain fibres transmit
Tissue damage also sends inhibitory signals to the SG
Rubbing the painful area -> sends A beta fibres which stimulate the SG -> send inhibitory signals to laminae in dorsal horn, which reduces pain going to thalamus

Question 5

Outline how pain is modulated centrally

Answer 5

Tissue damage stimulates A delta & C afferent nerves, which enter the dorsal horn and project to the thalamus, causing pain and sensation
Thalamus stimulates cortex & periaqueductal grey matter
Periaqueductal grey matter sends inhibitory signals to the dorsal horn via endogenous opioids -> reduces pain being sent to the thalamus

Question 6

Describe endogenous opioids

Answer 6

Enkephalins, endorphins and dynorphins 
Opioid receptors = G protein receptors 
Three receptor subtypes:
1) MOP/u
2) DOP/delta
3) KOP/K

Question 7

Describe the MOP receptor

Answer 7

Most important clinically & causes most side-effects
Found predominantly in the brainstem and thalamus
GPCR

Question 8

Describe the phosphorylation and uncoupling mechanism of opioid tolerance

Answer 8

Opioid binds to GPCR -> decreased cAMP -> decreased pain
ALSO: intracellular phosphorylation occurs, which changes the u receptors -> arrestin can bind and displace the G protein OR opioid may not have the same effect -> don’t get the same decrease in pain

Question 9

Describe cAMP production mechanism of opioid tolerance

Answer 9

When opioid is removed: massive increase in cAMP
Causes neuronal excitability
Causes withdrawal symptoms – cramping, sweating, vomiting, diarrhoea -> common cause of death in addicts

Question 10

Describe opioids

Answer 10

Exploit natural opioid receptors, either agonise or antagonise
Main therapeutic effects via u-receptors
Aim to modulate pain
Also indicated in: cough, diarrhoea & palliation

Question 11

List examples of opioids

Answer 11

Strong agonists – morphine, fentanyl
Moderate agonists – codeine
Mixed agonist-antagonist/partial agonist – buprenorphine
Antagonists – naloxone

Question 12

Describe the WHO analgesic ladder

Answer 12

Used for chronic pain management
Simple analgesia – paracetamol, NSAIDs
Weak opioid – codeine 
Strong opioid – morphine, fentanyl 
(NB: for neuropathic pain use different drugs – anticonvulsants, tricyclics etc)

Question 13

Describe morphine

Answer 13

Strong affinity to u receptors
Complete activation of u
Actions: analgesia, euphoria
Side effects: respiratory depression, emesis, GI tract, CVS, miosis & histamine release – caution in asthmatics

Question 14

Describe fentanyl

Answer 14

100x potency compared to morphine, higher affinity for u receptor
Less histamine release, sedation & constipation
Actions: analgesia, anaesthetic
Side effects: respiratory depression, constipation & vomiting

Question 15

Describe codeine

Answer 15

Approx. 1/10 potency of morphine
Actions: mild-moderate analgesia, cough depressant
Side effects: constipation, respiratory depression (worse in children)
NB: active metabolite of codeine requires CYP2D6 oxidation activity -> deficiency in this CYP enzyme means less active metabolite being produced & less analgesia

Question 16

Describe buprenorphine

Answer 16

Very high affinity for u receptor, long duration of action
Actions: moderate to severe pain, opioid addiction treatment
Side effects: respiratory depression, low BP, nausea & dizziness

Question 17

Describe naloxone

Answer 17

Competitive antagonism of opioid

Side effect: short half life, slow infusion

Question 18

Describe opioid overdose

Answer 18

Growing problem, large number of iatrogenic addicts
Respiratory depression most common cause of death
Naloxone infusion as treatment

Question 19

List contraindications of opioids

Answer 19

Hepatic failure
Acute respiratory distress
Comatose 
Head injuries 
Raised ICP

Question 20

Describe asthma

Answer 20

Chronic inflammatory airway disease
Intermittent airway obstruction and hyper-reactivity
Small airways
Reversible both spontaneously & with drugs

Question 21

Describe control of asthma, what should be considered before stepping up/down treatment?

Answer 21

Minimal symptoms during day and night
Minimal need for reliever medication
No exacerbations
No limitation of physical activity
Normal lung function
Aim for early control with stepping up OR down as required
Before stepping up or down: adherence, inhaler technique & eliminate/reduce trigger factors

Question 22

Describe inhaled corticosteroids

Answer 22

Regular preventer when reliever alone not sufficient
Pass through plasma membrane, activate cytoplasmic receptors, activated receptor then passes in to nucleus to modify transcription
Reduces mucosal inflammation, widens airways, reduces mucus
Reduces symptoms, exacerbations & prevents death

Question 23

What are the adverse effects, warnings, contraindications and important drug interactions of inhaled corticosteroids?

Answer 23

Adverse effects: can cause local immunosuppressive action -> candidiasis, hoarse voice
Warnings, contraindications: pneumonia risk possible in COPD at high doses
Important drug interactions: if taken correctly, very few significant ADRs

Question 24

List examples of inhaled corticosteroids

Answer 24

Beclomethasone
Budesonide
Fluticasone

Question 25

Describe the basic mechanism of how steroids work

Answer 25

Gene activation – increased activation of B2 receptors, anti-inflammatory mediators & also inhibit release of arachidonic acid Gene repression – inflammatory mediators: interleukins, chemokines & cytokines

Question 26

Describe inhaled corticosteroids pharmacokinetics

Answer 26

Poor oral bioavailability High affinity for glucocorticoid receptor If steroid is absorbed p.o: almost complete first pass metabolism But at high doses, all ICS have potential to produce systemic side effects

Question 27

Describe B2 agonists

Answer 27

SABA: symptom relief through reversal of bronchoconstriction, only to be used p.r.n. LABA: add on therapy to ICS and p.r.n. SABA Major action on airway smooth muscle & also mucus clearance by action of cilia Prevention of bronchoconstriction prior to exercise

Question 28

List examples of B2 agonists

Answer 28

Fast, short acting: salbutamol, terbutaline Fast, long acting: formoterol Slow, long acting: salmeterol

Question 29

What are the adverse effects, warnings, contraindications and important drug interactions of B2 agonists?

Answer 29

Adverse effects: adrenergic – fight or flight effects, SVT Warnings, contraindications: LABA should only be prescribed alongside ICS, alone can mask airway inflammation and near-fatal & fatal attacks; tachycardia may provoke angina Important drug interactions: B-blockers may reduce effects of B2 agonists

Question 30

Describe leukotriene receptor antagonists

Answer 30

Montelukast Alternative to LABA 2nd step in NICE guidelines Leukotrienes released by mast cells/eosinophils – increased bronchoconstriction, increased mucus, increased oedema Leukotriene receptor antagonist block CysLT1 at CYSLTR1

Question 31

What are the adverse effects, warnings, contraindications and important drug interactions of leukotriene receptor antagonists?

Answer 31

Adverse effects: headache, GI disturbance, dry mouth, hyperactivity Warnings, contraindications: used as an add on in specific circumstances Important drug interactions: no major drug interactions reported

Question 32

Describe tiotropium

Answer 32

Long acting muscarinic antagonist (acts at M3 receptors) – severe asthma & COPD Block vagally mediated contraction of airway smooth muscle Adverse effects: infrequent – anticholinergic effects (dry mouth, urinary retention, dry eyes)

Question 33

Describe theophylline

Answer 33

For chronic poorly controlled asthma Adenosine receptor antagonist, decreases bronchoconstriction Warnings, contraindications: narrow therapeutic index, arrhythmias Important drug interactions: CYP450 inhibitors – increase concentrations of theophylline

Question 34

Describe self management plans for asthmatics

Answer 34

Written instructions on when and how to step up AND down treatment Should be reviewed following treatment for exacerbation and on discharge from hospital following acute attack

Question 35

List the treatment for acute severe and life-threatening asthma

Answer 35

Oxygen High dose B2 agonist Oral steroids (prednisolone) should be prescribed minimum 5 days Nebulised ipratropium bromide (short acting muscarinic antagonist) Consider i.v. aminophylline is life threatening/near fatal & no success with above – caution if taking p.o. theophylline

Question 36

List the 5 tasks of management for COPD

Answer 36

``` Confirm diagnosis Smoking cessation Breathlessness score Vaccination Medication ```

Question 37

Describe the treatment of acute exacerbations of COPD

Answer 37

Nebulised salbutamol and/or ipratropium should be prescribed (if patient is hypercapnic/acidotic nebuliser should be driven by air & not oxygen) Oral steroids – can be less effective than asthma due to reduced action on neutrophils Antibiotics Review of chronic treatment & action plan

Question 38

List inhaler options

Answer 38

Pressurised metered dose inhalers (pMDI) -inhalation and actuation of device, slow breath in and hold, can be used with a spacer to improve delivery Breath-actuated pMDI -automatic actuation upon inspiration Dry powder inhalers (DPI) -micro-ionised drug plus carrier powder, own inspiratory flow – fast deep inhalation

Question 39

List features of acute severe asthma

Answer 39

Unable to complete sentences Peak flow 33-50% best or predicted Respiratory rate > 25 Heart rate > 110/min

Question 40

Describe why inhaled drug particles that are too small & too big are ineffective in asthma management

Answer 40

Too small = inhaled into alveoli and exhaled without being deposited in the lungs Too big = deposited in the mouth and oropharynx