Pharm-00A15: Describe the effects of opioids on the respiratory system 75%

Opioids → exogenous substance (natural and synthetic) that has an affinity for opioid receptors

Mechanism of action:
- Opioid agonists act on opioid receptors (μ, κ, δ) which are located widespread in CNS
(supraspinal and spinal locations) → all are membrane-bound GPCR (Gi) → receptor
activation causes inhibition of adenylyl cyclase → ↓ IC [cAMP] → causes (i) opening of
VG-K+ channels and (ii) closure of VG-Ca2+ channels → ↓ neuronal activity
- μ and δ receptors are 1°ly responsible for respiratory effects

Effects of opioids on respiratory system:

Important to note → * Effects on respiratory system are dose-dependent

* Respiratory effects occur within therapeutic doses for analgesia →
this is b/c opioids have a narrow therapeutic index
* Tolerance to respiratory effects of opioids occurs

(1) Respiratory depression → due to direct inhibition of medullary ventilatory centres →

produces ↓ RR with compensatory ↑ TV, which leads to net ↓ MV (due to incomplete
compensatory ↑ MV) → causes apnoea (and death 2° to respiratory arrest) at excessive doses

Note: * Phenylpiperidine-derivatives (Eg. pethidine, fentanyl, remifentanil, Etc.) more potent

respiratory depressants cf. morphine or codeine
* Fentanyl and sufentanil → risk of persistent/recurrent respiratory depression 2° to
washout from pulmonary stores
* Tramadol and oxycodone have minimal respiratory depression

(2) ↓ ventilatory drive to ↑ PaCO2 and ↓ PaO2 → due to ↓ ACh from medullary neurons in
response to ↑ CO2 and/or ↓ O2 → causes ↑ resting PaCO2 (2° to right shift in MV vs PaCO2)
and ↓ resting PaO2

Note – CO2 chemoreceptor sensitivity is affected more cf. O2 → thus, supplementary O2

removes hypoxic stimulus to breathe → potentiates respiratory depression

(3) Anti-tussive effects → due to depression of medullary cough centre → prominent with codeine

(4) Chest and abdominal wall muscle rigidity (causing difficult PPV) → due to opioid receptor
interaction with DA and GABA pathways in substantia nigra and striatum → prominent with
phenylpiperidine-derivatives (Ie. remifentanil, fentanyl, alfentanil, Etc.) at high-doses

(5) Impaired upper airway reflexes → due to sedation and suppression of cough reflex →
permits instrumentation of airway BUT risk of aspiration and airway obstruction

(6) ↑ airway resistance → due to direct bronchial SM effect and histamine effect (2° to mast cell
degranulation), which causes bronchoconstriction (possess issue with asthma/COPD) →
prominent with morphine cf. phenylpiperidine-derivatives

(7) ↓ ciliary activity → mucous plugging

Effects on respiratory system vary with:

- (1) Type of opioid used (see above for examples) and doses used (↑ effects with ↑ doses)
- (2) Route of administration:
o Neuraxial opioids → Early respiratory depression (within 2 hr) occurs with lipid-
soluble opioids (Eg. fentanyl) due to systemic opioid absorption and subsequent
 interaction with opioid receptors in medulla; delayed respiratory depression (> 2
hrs) occurs with less lipid-soluble opioids (Eg. morphine) due to cephalad
migration of opioid and subsequent interaction with opioid receptors in medulla
o IV/IM opioids have faster onset and ↑ pronounced respiratory effects vs PO opioids
- (3) Lack of opioid tolerance → ↑ respiratory effects
- (4) Age → advanced ages have ↑ sensitivity to these effects due to immature BBB or ↑
opioid sensitivity
- (5) Co-morbidities (esp underlying respiratory disease, obesity, sleep apnoea,
encephalopathy, Etc.) → ↑ respiratory effects
- (6) Level of CNS stimulation → sleep, lack of pain, delirium, Etc. → ↑ respiratory effects
- (7) Concurrent use of drugs that cause sedation/respiratory depression (Eg. other
opioids, benzodiazepines, EtOH, volatile agents, IV induction agents, Etc.) → interact
additively or synergistically to cause respiratory effects