1. Opoid agonist and antagonits

2. WHO analgesic ladder Pain Pain persists Pain persists
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WHO analgesic ladder
Pain Pain persists Pain persists
or increases or increases
3. Strong opioid
± non-opioid
± adjuvant
2. Weak opioid
± non-opioid
± adjuvant
1. Non-opioid
± adjuvant 9

4. Classes of opoids agonists

5. .

7. Opioid analgesics
All drugs in this category act by binding to specific Opioid receptors in CNS to produce effects that mimic the action of naturally occurring substances, called endogenous opioid peptides or endorphins.
Exert their major effect by interacting with Opioid receptor in the CNS, and in other places such as GI tract and urinary bladder.
Opioids cause hyperpolarization of nerve cells, inhibiting nerve firing, and presynaptic inhibition of transmitter release.
Morphine causes analgesia, and patients treated with morphine are still aware of the presence of pain, but sensation is not unpleasant.

9. Opioid Analgesics: Indications
Main use: to alleviate moderate to severe pain
Cough centre suppression
Treatment of diarrhea
Balanced anaesthesia

11. Opioid Analgesics: Side Effects
Euphoria
CNS depression
Nausea and vomiting
Respiratory depression
Urinary retention
Diaphoresis and flushing
Pupil constriction (miosis)
Constipation
Itching

13. Repeated use of Morphine
Department of Pharmacology, DSMA
Repeated use of Morphine
Psychological dependence
Physical dependence
Tolerance
Withdrawal syndrome
Hyperalgesia???????

14. Tolerance/Dependence/Addiction
– Physiologic phenomenon resulting in progressive decline in potency of an opioid with continued use.
Addiction
– Psychological & behavioralsyndrome manifested by drug seeking behavior, loss of control of drug use, and continued use despite adverse effects.
Dependence
– Physiologic state
characterized by withdrawal symptoms upon abrupt discontinuation/ reduction of narcotic therapy.
• Abstinence syndrome
• Independent of tolerance

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

16. Pregnancy and elderly
If acetaminophen is insufficient, opioids are considered
acceptable during pregnancy provided they are given for a short duration.
Chronic opioid use can result in fetal dependence, premature delivery and growth retardation.
In elderly
Opioid analgesics have an increased likelihood of more profound adverse effects as well as prolonged durations of action. Therefore it is best not to select an opioid.
If it is necessary, reduced doses must be utilized.

17. Subclass
Mechanism of Action
Effects
Clinical Applications
Pharmacokinetics, Toxicities
Strong opioid agonists 
  Morphine
Strong -receptor agonists
Analgesia relief of anxiety
sedation
slowed gastrointestinal transit
Severe pain adjunct in anesthesia (fentanyl, morphine) pulmonary edema (morphine only) maintenance in rehabilitation programs (methadone only)
First-pass effect duration 1–4 h except methadone, 4–6 h
Toxicity: Respiratory depression
severe constipation addiction liability convulsions
  Methadone
  Fentanyl
  Hydromorphone, oxymorphone: Like morphine in efficacy, but higher potency 
  Meperidine: Strong agonist with anticholinergic effects 
  Sufentanil, alfentanil, remifentanil: Like fentanyl but shorter durations of action 
Partial agonists 
  Codeine
Less efficacious than morphine
Like strong agonists
weaker effects
Mild-moderate pain
cough
Like strong agonists, toxicity dependent on genetic variation of metabolism

18. Opioids Strong opioids Weak opioids Oxycodone Codeine Morphine
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Opioids
Strong opioids
Oxycodone
Morphine
Methadone
Fentanyl
Mepiridine
Weak opioids
Codeine
Tramadol 17

19. Morphine
Opioids induce sleep, and in clinical situations when pain is present and sleep is necessary, morphine may be used to supplement the sleep-inducing properties of hypnotic agents
Morphine relieves diarrhea by decreasing the motility and increasing the tone of the intestinal smooth muscles
Morphine produce a powerful sense of euphoria and well-being.
Morphine is also used in the treatment of acute pulmonary edema, intravenous morphine is dramatically relieve dyspnea cause by pulmonary edema associated with left ventricular failure.

20. Kidney
Morphine has 2 biologically active metabolites, morphine-6- glucuronide and morphine-3-glucuronide.
Morphine-6-glucuronide binds to the opioid receptor and is believed to contribute to the effects of the parent compound. Morphine-3-glucuronide does not bind to the receptor and is believed to contribute in some cases to adverse effects such as myoclonus and confusion.
Usually, the metabolites are considered a clinical issue only when their concentrations in the blood are likely to fluctuate differently than the concentration of the parent compound. This can occur during renal insufficiency,

21. Hydromorphone
may be preferred over morphine for patients with decreased renal clearance, to preempt the potential for toxicity from morphine metabolite accumulation.

22. (Mepiridine, pethidine)
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(Mepiridine, pethidine)
Repetitive dosing leads to accumulation of the toxic metabolite normeperidine (normeperidine)
Norpethidine accumulation causes
CNS hyper-excitability, subtle mood changes,
Tremors, Multifocal myoclonus, Seizures
Common with repeated large doses, eg 250 mg per day.
It is renally cleared, and use of meperidine in patients with kidney disease is not recommended. 25

23. Mepiridine
Obstetric labor
Shivering

24. Methadone NMDA receptors blocking Monoaminergic reuptake transporters.
Treat difficult to treat pain, especially when morphine failed.
Widely used in opioids abuse.
why?????

25. Source: NSW Department of Health (2007) NSW Drug and Alcohol Withdrawal Clinical Practice Guidelines25

26. Tramadol Analgesic action mechanism Not fully understood
Weak affinity for -opioid receptor
Inhibition of norepinephrine reuptake
→ 2-adrenoreceptor activation
→ act synergistically with tramadol’s opioid receptor activation
→ analgesia
Advantage
Less respiratorpsychomotor recoveryy depression, nausea, vomiting, constipation
Rapid
Moderate pain treatment : as effective as morphine
Severe pain treatment : less effective than morphine

27. Peripherally Acting Opioid
Opioid receptor – outside central nerve system
Peripherally acting opioid agonist
→ analgesia without CNS side effect
Loperamide
-opioid receptor agonist
Not cross blood-brain barrier
Treatment : inflammation-induced hyperalgesia
Relieve diarrhea

31. PARTIAL AGONISTS AND MIXED AGONIST–ANTAGONISTS
Partial agonists bind to the opioid receptor, but have less intrinsic activity than full agonists
Drugs that stimulate one receptor but block another are termed mixed agonist–antagonists.
The effects of these drugs depend on previous exposure to opioids.
In individuals who have not received opioids (naïve patients), mixed agonist–antagonists show agonist activity and are used to relieve pain.
In the patient with opioid dependence, the agonist–antagonist drugs may show primarily blocking effects (that is, produce withdrawal symptoms).

32. Buprenorphine
Buprenorphine [byoo-pre-NOR-feen] is classified as a partial agonist, acting at the μ receptor. It acts like morphine in naïve patients,
but it can also precipitate withdrawal in users of morphine or other full opioid agonists.
Pentazocine
Pentazocine [pen-TAZ-oh-seen] acts as an agonist on κ receptors and is a weak antagonist at μ and δ receptors.
Pentazocine promotes analgesia by activating receptors in the spinal cord, and it is used to relieve moderate pain.
It may be administered either orally or parenterally.
Nalbuphine and butorphanol Nalbuphine [NAL-byoo-feen] and butorphanol [byoo-TOR-fa-nole] are mixed opioid agonist–antagonists.

33. Other analgesic Tramadol
Tramadol [TRA-ma-dole] is a centrally acting analgesic that binds to the μ opioid receptor.
The drug undergoes extensive metabolism via CYP450 2D6, leading to an active metabolite with a much higher affinity for the μ receptor than the parent compound.
In addition, it weakly inhibits reuptake of norepinephrine and serotonin.
It is used to manage moderate to moderately severe pain.
Its respiratory depressant activity is less than that of morphine.
Naloxone can only partially reverse the analgesia produced by tramadol or its active metabolite.
As with other agents that bind the μ opioid receptor, tramadol has been associated with misuse and abuse.

34. Opoids Antagonists
The opioid antagonists bind with high affinity to opioid receptors, but fail to activate the receptor-mediated response.
Administration of opioid antagonists produces no profound effects in normal individuals.
However, in patients dependent on opioids, antagonists rapidly reverse the effect of agonists, such as morphine or any full μ agonist, and precipitate the symptoms of opioid withdrawal.

36. A. Naloxone
Naloxone [nal-OX-own] is used to reverse the coma and respiratory depression of opioid overdose.
It rapidly displaces all receptor-bound opioid molecules and, therefore, is able to reverse the effect of a morphine overdose. Within 30 seconds of IV injection of naloxone,
the respiratory depression and coma characteristic of high doses of morphine are reversed, causing the patient to be revived and alert.
Naloxone has a half-life of 30 to 81 minutes; therefore, a patient who has been treated and recovered may lapse back into respiratory depression.
Naloxone is a competitive antagonist at μ, κ, and δ receptors, with a 10-fold higher affinity for μ than for κ receptors.
This may explain why naloxone readily reverses respiratory depression with only minimal reversal of the analgesia that results from agonist stimulation of κ receptors in the spinal cord.
There is little to no clinical effect seen with oral naloxone,
upon IV administration, opioid antagonism occurs, and the patient experiences withdrawal.
This is why naloxone has been combined with oral opioids to deter IV drug abuse.

37. B. Naltrexone
Naltrexone [nal-TREX-own] has actions similar to those of naloxone.
It has a longer duration of action than naloxone,
a single oral dose of naltrexone blocks the effect of injected heroin for up to 24 hours.
Naltrexone in combination with clonidine (and, sometimes, with buprenorphine) is used for rapid opioid detoxification.
Although it may also be beneficial in treating chronic alcoholism by an unknown mechanism, benzodiazepines and clonidine are preferred.
Naltrexone can lead to hepatotoxicity.