Opioids

1. OPIOIDS

2. MORPHINE
 Produced as Hydrochloride or sulphate salts.
 Pharmacology
 Occurs naturally as opium, from the poppy
flower.
 A phenantherene alkaloid.

3. Actions on the CNS
 A range of stimulant and depressant actions at
all levels of the CNS.
 Depressant actions on the cerebral cortex may
produce calm, reducing fear and anxiety.
 Can also lead to a loss of mental
concentration, and ability to deal with complex
reasoning.
 Impairs mental and physical performances.

4. Contd…
 Morphine and morphine-6-glucuronide exert a
full agonist action at μ opioid receptors at the
spinal cord, peri aqueductal grey, thalamic and
cortical regions.
 Spinal κ (kappa) receptors may contribute to
the spinal component.
 Higher doses produce dysphoria and
sometimes hallucinatory effects at δ(delta) and
κ.

5. Contd…
 Effect on the cerebellum is mainly depressant,
causing an ataxic gait by inhibiting motor
coordination.
 Depresses the respiratory centre and becomes
less sensitive to the stimulant effects of carbon
dioxide.
 It is detectable even after the smallest effective
analgesic doses of morphine and overdosage
– death.

6. Contd…
 Also depresses the cough centre, but others
eg. Codeine and diamorphine do this more.
 Triggers the chemoreceptor emetic trigger
zone causing nausea and vomiting.
 Causes pupillary constriction, morphine
poisoning brings about pin-point size, which
dilate again only when morphine effect wears
off, is antagonized or when asphyxia occurs.

7. Analgesia
 Analgesic effect reaches its peak about 20
minutes after IV injection .
 90minutes after IM or SC injection.
 Duration of action-4 hours.
 Best effects are when dosage precedes the
onset of painful stimuli.

8. Contd…
 It relieves pain by;
1. Raising the threshold of pain
2. Altering the pattern of reaction to pain
3. Induction of sleep
4. Induction of hypercapnia

9. Side effects
 Reduction in systemic BP.
 Morphine induced bradycardia results from
increased activity over the vagal nerves.
 Also direct depression on the SAN and acts to
slow conduction of cardiac impulses through
the AVN.
 Combination of an opioid agonist such as
morphine/fentanyl with nitrous oxide results in
CVS depression.

10. Contd…
 Ventilatory depression
 Is rapid and persists for several hours
 High doses cause apnoea
 Characterised by a decreased frequency of
breathing and a compensatory increase in Vt.

11.  In the absence of hypoventilation , cerebral
blood flow and possibly ICP.
 Use with caution in patients with head injury
because of their;
1. Associated effects on wakefulness
2. Production of miosis
3. Depression of ventilation and associated
increase in ICP if PaCO2 increases.

12.  Spasm of the biliary smooth muscle resulting
in an increase in interbiliary pressure .
 GIT- spasm of the GI smooth muscles causing
constipation, biliary colic and delayed gastric
emptying.
 Nausea and vomiting
 Increases the tone and peristaltic activity of the
ureter.

13.  Vasodilatation of cutaneous blood vessels of
the skin, face, neck and upper chest.
 Caused by the release of histamine
 Crosses the placenta, can cause depression in
the neonate.

14. Drug interactions
 Ventilatory depressant effects of some opioids
maybe exaggerated by amphetamines,
phenothiazines, MAOIs and TCA.

15. Overdose
 Ventilatory depression-slow breathing
frequency and apnoea
 Pupils are symmetric and miotic unless severe
arterial hypoxaemia is present-mydriasis.
 Flaccid skeletal muscles and upper airway
obstruction can occur.
 Overdose triad= miosis, hypoventilation and
coma: mechanical ventilation with oxygen and
administration of naloxone.

16. Pethidine
 Synthetic opioid agonist at κ and μ receptors.
 Derived from phenylpiperidine.
 Structurally similar to atropine and possess a
mild atropine like antispasmodic effect.

17. Pharmacokinetics
 About 1/10 as potent as morphine.
 80-100mg IM being equivalent to about 10mg
of morphine.
 Duration of action 2-4 hours.
 In equal analgesic doses it produces much
sedation, euphoria, nausea and vomiting,
depression of ventilation as doses of
morphine.

18. Metabolism
 Hepatic metabolism is extensive with~90%
undergoing demethylation to normeperidine
and hydrolysis to meperidinic acid.
 Normeperidine undergoes hydrolysis to
normeperidinic acid.
 Excretion-urinary and is pH dependent.
 Reduced renal function can predispose to
accumulation of normeperidine.

19. Contd…
 Normeperidine elimination ½ time-15 hours
(35hours in patients with renal failure). And
can be detected in urine for as long as 3 days
after administration.
 Elimination ½ time of meperidine is 3-5 hours
 About 60% is protein bound.
 Elderly patients exhibit reduced protein binding
:. Increased plasma concentration of free drug
and an increased sensitivity to the opioid.

20. Clinical uses
 Analgesia during and after surgery
 Suppresses post op shivering that increases
metabolic oxygen consumption.
 Antishivering most likely is due to stimulation
on κ receptors.
 Not useful in treatment of diarrhoea or as
antitussive.
 At high doses it has significant negative
inotropic effects plus histamine release in
some patients.

21. Side effects
 Orthostatic hypotension due to interference with
compensatory SNS reflexes.
 Rarely causes bradycardia but may cause
increase in HR due to atropine-like effects.
 Reduction in myocardial contractility at high
doses.
 Ventilatory depressant
 crosses the placenta
 Constipation and urinary retention is less than
with morphine
 Biliary tract colic
 Mydriasis, dryness of the mouth.

22. Fentanyl
 Phenylpiperidine derivative
 Synthetic opioid agonist
 structurally related to pethidine
 It is 75-125* more potent than morphine.

23. Pharmacokinetics
 Single IV dose has a more rapid onset and
shorter duration of action than morphine.
 Is more lipid soluble compared to morphine :.
Facilitating passage across the BBB and more
rapid onset of action.
 Shorter duration of action shows its rapid
redistribution to inactive sites such as fat and
skeletal muscles:. Associated reduction in the
plasma concentration of the drug.

24. Contd…
 With multiple Iv doses or infusion there is
progressive saturation of the inactive tissue
sites occur :. The plasma concentration of
fentanyl does not reduce rapidly and the
duration of analgesia and ventilatory
depression maybe prolonged.

25. Metabolism
 Metabolised by N-demethylation-norfentanyl-
structurally similar to normeperidine.
 Has less analgesic activity.
 Excreted by the kidneys.
 Elimination t ½ time is longer than for
morphine, 3.1-6.6 hours.
 Due to its greater lipid solubility :.more rapid
passage into tissues than less lipid soluble
morphine.

26. Clinical uses
 analgesia: low doses 1-2mg/kg Iv
 Sole anaesthetic due to stability of
haemodynamics due to;
1. Lack of myocardial depressant effects
2. Absence of histamine release
3. Suppression of the stress responses to
surgery.

27. Contd…
 Disadvantage of being the sole anaesthetic
1. Possible patient awareness
2. Post op ventilatory depression.
 Transmucosal preparation :-5-20μg/kg.
 Transdermal patch: -75-100μg/kg

28. Side effects
 Ventilatory depression
 Bradycardia
 Allergic reactions-rare
 Seizure activity
 Modest increase in ICP

29. Remifentanil
 Selective μ opioid agonist
 Structurally unique because it has an ester
linkage which renders it susceptible to
hydolysis by non-specific plasma and tissue
esterases to inactive metabolites:.
1. Short duration of action
2. Non cumulative effects
3. Rapid recovery after discontinuation

30. Pharmacokinetics
 Characterised by a small volume of
distribution; rapid clearance; low variability
compared to others
 Rapid metabolism and does not accumulate

31. Metabolism
 By non specific plasma and tissue esterases
to inactive metabolites
 Undergoes renal excretion
 Not affected in renal or hepatic failure patients.
 99.8% is eliminated during distribution (0.9
min).
 Elimination ½ time- 6.3 minutes

32. Clinical uses
 Profound analgesic effects
 For patients at risk for suppression of the transient
SNS response direct laryngoscopy and tracheal
intubation
 Long operations when quick recovery time is
desired.
 Together with midazolam for sedation
 Not recommended for spinal or epidural.
 Before cessation of remi, long acting opioid
maybe administered to ensure analgesia.

33. Side effects
 Rapid onset- muscle rigidity if large doses are
administered by rapid IV injection
 Nausea, vomiting, ventilatory depression; mild
reduction in systemic BP, Hr.
 Does not cause histamine release
 ICP/IOP are not changed by remi.
 CBF and cerebral metabolic oxygen
requirements are reduced by remi to a degree
similar to other opioids.

34. Tramadol
 Centrally acting analgesic with low affinity for
mu(μ) opioid receptors.
 5-10* less potent than morphine as an
analgesic.
 Analgesic properties may reflect the ability to
inhibit nor-e and 5HT3 neuronal uptake and to
facilitate 5HT3 release :. May affect central
catecholamine pathways directly by preventing
nor e uptake.

35. Contd…
 Production of analgesia with the absence of
depression of ventilation and a low potential
for the development of tolerance, dependence,
abuse.
 Major metabolite- O-desmethyltramadol
 Administration-IM,IV,PO.
 Moderate-severe pain.
 Cannot prevent intra-op awareness.
 High incidence of nausea and vomiting
 Chronic pain treatment

36. Opioid antagonists
 Naloxone
 Naltrexone
 Nalmefene

37. Naloxone
 Used to treat
1. Opioid induced ventilatory depression
2. As above in a neonate whose mother had
been given an opioid.
3. Management of deliberate opioid overdose
4. Detection of suspected physical dependence

38. Contd…
 1-4μg/kg IV promptly reverses opioid induced
analgesia and ventilatory depression
 Short duration of action 30-45 min due to rapid
removal from the brain
 Infusion 5μg/kg/hr.
 Metabolised in liver by glucuronic acid to form
naloxone-3-glucuronide
 Elimination ½ time 60-90minutes

39. Side effects
 Reversal of analgesia, nausea and vomiting
especially after a bolus
 CVS-increases SNS activity due to abrupt
reversal and sudden perception of pain :. HR,
hypertension, pulmonary oedema, arrythmias.
 Crosses the placenta and may cause acute
withdrawal in the neonate in an opioid
dependent parturient.

40. Naltrexone
 Highly effective orally, producing sustained
antagonism of the effects of opioid agonists for
as long as 24hours.

41. Nalmefene
 Pure opioid antagonist,
 6-methylene analogue to naltrexone
 Equipotent to naloxone
 Dose 0.25μg/kg IV every 2-5minutes: not to
exceed 1μg/kg.

42. Contd…
 Longer duration of action than naloxone hence
a greater degree of protection from delayed
depression of ventilation due to residual
effects of the opioid.
 Elimination t ½: 8-10hours, slower clearance.
 Metabolised by hepatic conjugation with <5%
excreted unchanged in urine.
 Pulmonary oedema may occur.