This document summarizes the pharmacology of several opioid analgesics and antagonists. It describes how morphine, pethidine, fentanyl, remifentanil, and tramadol work as agonists at mu opioid receptors to produce analgesia and other central nervous system effects. It also discusses the metabolism, clinical uses, side effects, and antagonism by naloxone, naltrexone, and nalmefene of these 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.