opoids and analgesics

1. 1

2. OPIOID ANALGESICS &
ANTAGONISTS
Dr. Muhammad Aitmaud uddolah Khan
M.D. M.Phil
Assistant Professor Pharmacology
Baqai Medical University
Karachi

3. History of Opioids
• Opium is extracted from poppy seeds
(Paper somniforum)
• Used for thousands of years to produce:
– Euphoria
– Analgesia
– Sedation
– Relief from diarrhea
– Cough suppression

4. History cont’d
• Used medicinally and recreationally from
early Greek and Roman times
• Opium and laudanum (opium combined
with alcohol) were used to treat almost all
known diseases
• Morphine was isolated from opium in the
early 1800’s and since then has been the
most effective treatment for severe pain

5. History and Background
• Invention of the hypodermic needle in
1856 produced drug abusers who self
administered opioids by injection
• Controlling the widespread use of opioids
has been unsuccessful because of the
euphoria, tolerance and physiological
dependence that opioids produce

6. Terminology
• “Opium” is a Greek word meaning “juice,”
or the exudate from the poppy
• “Opiate” is a drug extracted from the
exudate of the poppy
• “Opioid” is a natural or synthetic drug that
binds to opioid receptors producing
agonist effects

7. Natural opioids occur in 2 places:
1) In the juice of the opium poppy (morphine
and codeine)
2) As endogenous endorphins
• All other opioids are prepared from either
morphine (semisynthetic opioids such as
heroin) or they are synthesized from
precursor compounds (synthetic opioids
such as fentanyl)

8. Mechanism of action
• Activation of peripheral nociceptive fibers causes
release of substance P & other pain-signaling
neurotransmitters from nerve terminals in the
dorsal horn of the spinal cord
• Release of pain-signaling neurotransmitters is
regulated by endogenous endorphins or by
exogenous opioid agonists by acting
presynaptically to inhibit substance P release,
causing analgesia
• Opioid agonists produce analgesia by binding to
specific G protein-coupled receptors that are
located in brain & spinal cord regions involved in
the transmission and modulation of pain

9. Primary Effect of Opioid Receptor
Activation
• Reduction or inhibition of neurotransmission, due to
largely opioid-induced presynaptic inhibition of
neurotransmitter release
• Involves changes in transmembrane ion
conductance
– Increase potassium conductance
(hyperpolarization)
– Inactivation of calcium channels

10. Pharmacological Effects
• Sedation and anxiolysis
– Drowsiness and lethargy
– Apathy
– Cognitive impairment
– Sense of tranquility
• Depression of respiration
– Main cause of death from opioid overdose
– Combination of opioids and alcohol is especially dangerous
• Cough suppression
– Opioids suppress the “cough center” in the brain
• Pupillary constriction
– pupillary constriction in the presence of analgesics is
characteristic of opioid use

11. Pharmacological effects cont’d.
• Nausea and vomiting
– Stimulation of receptors in an area of the medulla called the
chemoreceptor trigger zone causes nausea and vomiting
– Unpleasant side effect, but not life threatening
• Gastrointestinal symptoms
– Opioids relieve diarrhea as a result of their direct actions on the
intestines
• Other effects
– Opioids can release histamines causing itching or more severe
allergic reactions including bronchoconstriction
– Opioids can affect white blood cell function and immune function

12. Three Opioid Receptors
• Mu (µ)
• Kappa (κ)
• Delta (δ)

13. Mu-Receptor: Two Types
• Mu-1
– Located outside spinal
cord
– Responsible for central
interpretation of pain
• Mu-2
– Located throughout
CNS
– Responsible for
respiratory depression,
spinal analgesia,
physical dependence,
and euphoria

14. Kappa Receptor
• Supraspinal and spinal analgesia;
• Psychotomimetic effects
• Slowed gastrointestinal transit
• Little or no respiratory depression
• Little or no dependence
• Dysphoric effects

15. Delta Receptor
• Supraspinal and spinal analgesia;
• Modulation of hormone & neurotransmitter
release
• Delta agonists show poor analgesia and
little addictive potential

16. Mu and Kappa Receptor Activation
Response Mu-1 Mu-2 Kappa
Analgesia
Respiratory
Depression
Euphoria
Dysphoria
Decrease GI
motility
Physical
Dependence

17. Mu and Kappa Receptors
DRUGS MU KAPPA
Pure Agonists Agonist Agonist
Agonist-
Antagonist
Antagonist Agonist
Pure
Antagonists
Antagonist Antagonist

18. Terminology
• Pure Agonist: has affinity for binding plus efficacy
• Pure Antagonist: has affinity for binding but no efficacy;
blocks action of endogenous and exogenous ligands
• Mixed Agonist-Antagonist: produces an agonist effect at
one receptor and an antagonist effect at another
• Partial Agonist: has affinity for binding but low efficacy

19. AGONISTS
*Morphine
*Heroin
*Hydromorphone
*Fentanyl
*Codeine

20. General Pharmacokinetics
LATENCY TO ONSET
• *oral (15-30 minutes)
• *intranasal (2-3 minutes)
• *intravenous (15 – 30 seconds)
• *pulmonary-inhalation (6-12 seconds)
DURATION OF ACTION – anywhere between 4
and 72 hours depending on the substance
• Metabolism – hepatic via phase 1 and phase 2
biotransformations to form a diverse array of
metabolites ( eg., morphine to morphine-6-
glucuronide)

21. Morphine
PHARMACOKINETICS
Routes of administration (preferred)
• Oral
latency to onset –(15 – 60 minutes )
• It is also sniffed, swallowed and injected
• Duration of action – ( 3 – 6 hours)
• First-pass metabolism results in poor
• Availability from oral dosing
• 30% is plasma protein bound
EFFECTS AND USES
• Symptomatic relief of moderate to severe pain
• Relief of certain types of labored breathing
• Suppression of severe cough (rarely)
• Suppression of severe diarrhea
• AGONIST for mu, kappa, and delta receptors

22. Hydromorphone
PHARMACOKINETICS
Routes of administration (Preferred)
• Oral
Latency to onset (15 – 30 minutes)
• Intravenous
Duration of Action (3-4 hours)
Peak effect (30-60 minutes)
PROPERTIES AND EFFECTS
• Potent analgesic like morphine but is 7-10 times as
potent in this capacity
• Used frequently in surgical settings for moderate to
severe pain. (cancer, bone trauma, burns, renal colic.)

23. Fentanyl
Pharmacokinetics
Routes of Administration
• Oral, and transdermal (possibly intravenous)
• Highly lipophilic
• Latency to onset (7-15 minutes oral; 12-17 hours
• Transdermal
• Duration of action ( 1-2 hours oral; 72 transdermal)
• 80 – 85% plasma protein bound
• 90 % metabolized in the liver to inactive metabolites
Other properties
• 80 times the analgesic potency of morphine & 10 times the
analgesic potency of hydromorphone
• High efficacy for mu 1 receptors
• Most effective opiate analgesic

24. Antagonists
• Naloxone
• Naltrexone

25. Naltrexone
PHARMACOKINETICS
• *latency to onset (oral tablet 15-30 min.)
• *duration of action 24-72 hours
• *peak effect (6-12 hours)
EFFECTS
• *Reverses the psychotomimetic effects of opiate
agonists
• * Reverses hypotension and cardiovascular instability
secondary to endogeneous endorphins (potent
vasodilators)
• *inhibits Mu, Delta, and Kappa receptors

26. Clinical Use of Opioid
Analgesics
Analgesia
• Cancer
• Obstetric labor
• Acute & severe pain of renal & biliary colic

27. Acute Pulmonary Edema
• Morphine (IV) provides relief in dyspnea
from pulmonary edema associated with
left ventricular heart failure
• If respiratory depression is a problem,
furosemide may be preferred for the
treatment of pulmonary edema

28. Cough
• Suppression of cough can be obtained at
doses lower than those needed for
analgesia

29. Diarrhea
• Diarrhea from almost any cause can be
controlled with the opioid analgesics
• Diphenoxylate or loperamide, are usually
used

30. Shivering
• Although all opioid agonists have some
tendency to reduce shivering, meperidine
is reported to have the most pronounced
antishivering properties

31. Applications in Anesthesia
• The opioids are frequently used as premedicant
drugs before anesthesia & surgery because of
their sedative, anxiolytic, & analgesic properties
• They are also used intraoperatively both as
adjuncts to other anesthetic agents &, in high
doses (eg, 0.02–0.075 mg/kg of fentanyl), as a
primary component of the anesthetic regimen

32. Toxicity & Undesired Effects

33. Tolerance
• Tolerance is a diminished responsiveness to the drug’s
action that is seen with many compounds
• Tolerance can be demonstrated by a ↓ed effect from a
constant dose of drug or by an ↑se in the minimum drug
dose required to produce a given level of effect
• Physiological tolerance involves changes in the binding
of a drug to receptors or changes in receptor
transductional processes related to the drug of action
• This type of tolerance occurs in opioids

34. Tolerance continued
• Molecular basis of tolerance involves
glutaminergic mechanisms (glutamate-excitatory
amino acid neurotransmitter)
• 1997, Gies and colleagues stated that activation
of glutamate NMDA receptors correlates with
resistance to opioids and the development of
tolerance
• NMDA receptor blocker ketamine prevented the
development of this late-onset and long-lasting
enhancement in pain sensitivity after the initial
analgesia effect

35. Tolerance continued
• Thus, glutaminergic NMDA receptors play important role
in the development of tolerance to the continuous
presence of opioid
• Cross-tolerance is the condition where tolerance for one
drug produces tolerance for another drug – person who
is tolerant to morphine will also be tolerant to the
analgesic effect of fentanyl, heroin, and other opioids
• * note that a subject may be physically dependent on
heroin can also be administered another opioid such as
methadone to prevent withdrawal reactions
• Methadone has advantages of being more orally
effective and of lasting longer than morphine or heroin

36. Tolerance continued
• Methadone maintenance programs allow heroin users
the opportunity to maintain a certain level of functioning
without the withdrawal reactions
• Toxic effects of opioids are primarily from their
respiratory depressant action and this effect shows
tolerance with repeated opioid use
• Opioids might be considered “safer” in that a heroin
addicts drug dose would be fatal in a first-time heroin
user

37. Dependence
• Physiological dependence occurs when the drug
is necessary for normal physiological functioning
– this is demonstrated by the withdrawal
reactions
• Withdrawal reactions are usually the opposite of
the physiological effects produced by the drug

38. Withdrawal Reactions
Acute Action
• Analgesia
• Respiratory Depression
• Euphoria
• Relaxation and sleep
• Tranquilization
• Decreased blood pressure
• Constipation
• Pupillary constriction
• Hypothermia
• Drying of secretions
• Reduced sex drive
• Flushed and warm skin
Withdrawal Sign
• Pain and irritability
• Hyperventilation
• Dysphoria and depression
• Restlessness and insomnia
• Fearfulness and hostility
• Increased blood pressure
• Diarrhea
• Pupillary dilation
• Hyperthermia
• Lacrimation, runny nose
• Spontaneous ejaculation
• Chilliness and “gooseflesh”

39. Dependence continued
• Acute withdrawal can be easily precipitated in drug
dependent individuals by injecting an opioid antagonist
such as naloxone or naltrexone – rapid opioid
detoxification or rapid anesthesia aided detoxification
• The objective is to enable the patient to tolerate high
doses of an opioid antagonist and undergo complete
detox in a matter of hours while unconscious
• After awakening, the person is maintained on orally
administered naltrexone to reduce opioid desire

40. Contraindications and Cautions
in Therapy
• Use of pure agonists with weak partial
agonists
• Use in patients with head injuries
• Use during pregnancy
• Use in patients with impaired pulmonary
function
• Use in patients with impaired hepatic or
renal function
• Use in patients with endocrine disease

41. SPECIFIC AGENTS
Strong Agonists
• Phenanthrenes (Morphine,
hydromorphone & oxymorphone)
• Phenylheptylamines (Methadone)
• Phenylpiperidines (Fentanyl; sufentanil,
alfentanil & remifentanil)
• Morphinans (Levorphanol)

42. Mild to Moderate Agonists
• Phenanthrenes (Codeine, oxycodone,
dihydrocodeine & hydrocodone)
• Phenylheptylamines (Propoxyphene)
• Phenylpiperidines (Diphenoxylate,
difenoxin, loperamide)

43. Opioids with Mixed Receptor Actions
• Phenanthrenes (Nalbuphine,
buprenorphine)
• Morphinans (Butorphanol)
• Benzomorphans (Pentazocine)