1. APOLLO COLLEGE OF PHARMACY, DURG
OPIOIDS, ANALGESICS AND
ANTAGONISTS
GUIDED BY-
Ms. Suruj kaoshik
Presented by-
Shweta kumari saw
2. What are opioids?
Opioids, sometimes called narcotics, are medications
prescribed by doctors to treat persistent or severe
pain. Opioids are a class of drugs that derive from, or
mimic, natural substances found in the opium poppy
plant. Opioids work in the brain to produce a variety
of effects, including pain relief. Opioids are a class of
drugs that are chemicals — natural or synthetic —
that interact with nerve cells that have the potential
to reduce pain.
3. Opioids are a dark brown resinous material obtained from poppy ( Papaver
somniferum) capsules.
4. Continue…
Opioid” is the proper term, but opioid drugs may also be
called opiates, painkillers or narcotics.
All opioids work similarly: They activate an area of nerve
cells in the brain and body called opioid receptors that
block pain signals between the brain and the body.
Examples of opioids include morphine, heroin, codeine,
oxycodone, hydrocodone and fentanyl.
5. Opiates are mainly used for their analgesic activity, but
they have many other effects throughout the body.
The body also naturally generates its own opioids ligands
such as endorphins and enkephalins.
Currently, there are 4 known receptor types:µ, δ, σ and К.
most often the terms opioids and opiates are used
synonymously.
Opiates are synthetic drugs derived from opium.
6.
7. Mechanism of action
Central and peripheral opioids receptors are coupled to inhibitory g-proteins.
The inhibition of adenylate cyclase activity lowers Ca2+ and results in
hyperpolarization.
Effects based on receptor types:
• The effects of binding with µ receptors include supraspinal analgesia,
respiratory depression, miosis and euphoria.
• The effects of К receptors include spinalanalgesia, sedation and miosis.
• Δ receptors induce cardiovascular stimulation and mydriasis, and can cause
dysphoria and hallucinations.
8. Opioids act both presynaptically and postsynaptically to produce an analgesic
effect. Presynaptically, opioids block calcium channels on nociceptive
afferent nerves to inhibit the release of neurotransmitters such as substance
P and glutamate, which contribute to nociception. Postsynaptically, opioids
open potassium channels, which hyperpolarize cell membranes, increasing the
required action potential to generate nociceptive transmission. The mu,
kappa, and delta-opioid receptors mediate analgesia spinally and
supraspinally.
opioids such as methadone also have activity at the N-methyl-D-aspartate
(NMDA) receptor. Methadone binds to the NMDA receptor and antagonizes the
effect of glutamate, which theoretically explains why methadone has efficacy
in the treatment of neuropathic pain above other opioids.
9.
10.
11. Classification of opioids
Opioids are classified into pure agonists, partial agonists, mixed agonist-
antagonist, and pure antagonists;
i. Pure agonists bind to µ receptors and exert maximum effect depending on
the dosage. They include morphine, fentanyl and pethidine.
ii. Partial agonists i.e, buprenorphine, are associated with partially agonistic
and antagonistic effects.
they have a ceiling effect, which means that the effect plateaus at a certain
dosage, and increasing the dosage will not increase its effects.
this effect is attributed to the extraordinary affinity of a partial agonist for
the µ receptor with lower intrinsic activity than morphine.
12. iii. Mixed agonist- antagonists
such as pentazocine act as antagonists at the µ receptor and agonists at the К
receptor with high intrinsic activity. Due to their antagonistic effect, they
prevent the binding of an agonist with the receptor and reverse its
pharmacological effects.
iv. Pure agonists
such as naloxone and naltrexone are competitive antagonists that bind to and
block all opioids receptors.
13.
14. Opioids antagonists
Opioid receptor antagonists block one or more of the opioid receptors
in the central or peripheral nervous system. Opioid receptors are
specific transmembrane neurotransmitter receptors that couple G-
proteins, which upon stimulation by endogenous or exogenous opioids,
leading to the intracellular process of signal transduction. The two
most commonly used centrally acting opioid receptor antagonists are
naloxone and naltrexone. Naloxone comes in intravenous,
intramuscular, and intranasal formulations and is FDA-approved for
the use in an opioid overdose and the reversal of respiratory
depression associated with opioid use. Naltrexone is available in both
oral and long-acting injectable formulations and is FDA-approved to
treat opioid and/or alcohol maintenance treatment.
15. The most commonly used peripheral opioid receptor
antagonist is methylnaltrexone, which is a potent
competitive antagonist acting at the digestive tract and is
also FDA-approved for the treatment of opioid-induced
constipation. This activity outlines the indications,
mechanism of action, methods of administration,
important adverse effects, contraindications, monitoring,
and toxicity of opioid antagonists, so providers can direct
patient therapy to optimal outcomes to combat opioid
overdose, misuse, or adverse effects.
16. Adverse effects
Accelerated protocols for medically supervised management of withdrawal
aim to reduce the transition time to naltrexone treatment, thereby reducing
patient inconvenience, lengths of inpatient or residential stay, and treatment
costs.
A low naloxone starting dose of just 0.1 mg intravenous is given, and the
patient is monitored for up to 30 minutes for signs of withdrawal. Typically,
symptoms present within 1-5 minutes. A doubled dose of 0.2 mg follows, and
the patient undergoes observation. Thirty minutes following, a final dose of
0.4 mg is given, and if the patient is asymptomatic, the assumption is that
the patient can safely receive naltrexone without fear of withdrawal
symptoms. The extended-release injectable version of naltrexone has found
increased favor among practitioners for opiate maintenance treatment as it
only needs dosing every four weeks.
17. Central and peripheral effects of opioids
The central effects of opioids are mediated via reduction
of pain transmission by stimulating opioids receptors.
the opioids activate the descending inhibitory system,
suppress the spinal nociceptive impulses, and modulate
the pain sensation in the limbic system.
Futhermore, opioids have a sedating and hypnotic effect.
in addition, they contain anxiolytic and euphoria inducing
components by inhibiting the respiratory centre and the
cough reflex, opioids induce respiratory depression and
have an antitussive effect.
18. Peripheral effects include analgesia, delayed gastric
emptying due to pyloric contraction and reduced gastric
motility and increased tone of the smooth musculature of
the gastrointestinal tract.
in addition, the tone of the bladder muscle and bladder
contractor muscle is increased.
Histamine release is also common, causing intense itch.
19. Interactions
Opioids interact with CNS depressants such as
hypnotics, phenothiazines, tranquilizers, and
especially alcohol, leading to enhanced sedation
and life threatening respiratory depression.
Motility inhibitors enhance the constipating
effects of opioids and cimetidine slows down the
breakdown of morphine.
20. indications
severe and extreme pain (nociceptive pain) i.e, surgical and tumor related
pain.
pain in cases of acute myocardial infarction and acute pulmonary oedema.
the WHO ladder governing the use of opioids.
The WHO ladder is used for the treatment of chronic pain.
it was originally created for the treatment of tumours.
It is, however, also applied for the treatment of chronic musculoskeletal pain
if NSRA drugs are contraindicated or if they do not provide adequate pain
relief.
21. Dependence and development of opioids tolerance result if opioids are only
administered during pain peaks.
therefore, pain management should consist of basic medication with
regarding products and on demand medication with fast acting agents of pain
peaks occurs.
Retarding products are frequently applied as patches that are changes every
27 hours.
these patches rake time to manifest their time to manifest their full
therapeutic effect, which continues for upto 16 hours after the patch is
removed.
22. Substance and their use with opioids
1. Low potency opioid alangesics
low potency opioids such as tilidine, dihydrocodeine, codeine and tramadol
are regulated under the controlled substance act and are administered for relief
of moderate to severe pain.
In comparison to morphine, they have lower efficacy i.e, they have lower
analgesic potency (RP<1)
Increasing the dosage of low potency opioids to a certain point leads to pain
relief equivalent to morphine.
This phenomenon is reffered to as the maximum attainable response.
In contrast, to high potency opioids any further increase in the dosage of low
potency opioids only results in stronger side effects without increasing analgesic
effect.
23. i. Tramadol has 0.1-0.2 fold higher analgesic potency compared with morphine.
However its most severe side effects are nausea and vomiting, whereas
constipation and respiratory depression are rare.
the effects of tramadol last 4-6 hours and it can be taken orally or
administered intravenously, intramuscularly or rectally.
ii. Dihydrocodeine and codeine have a relative potency of 0.3 and are used as
antitussive, because of their strong cough suppressant properties.
its effects last approx. 8-12 hours and it is administered orally. Headache is the
most common side effect of codeine. The most common side effect of
dihydrocodeine is constipation.
24. iii. Tilidine
analgesic potency of 0.2 and its effects last approx. 3 hours. Tilidine is
metabolized to nortilidine via hepatic conversion. Tilidine is available in fixed
combination with the opioid antagonist naloxone. Upon oral intake of a normal
dose of tilidine, naloxone is inactivated by the first pass effect in the liver and
nortilidine is effective. It is abused via intravenous administration, however
naloxone is effective as the hepatic inactivation of naloxone is delayed.
iv. Pentazocine and pethidine
only mediate postoperative analgesia. Both have a short duration of action
and may induce hallucinations even though they are mild opioids, they are
subject to the CSA.
25. 2. High potency opioids
i. Morphine
rapidly absorbed after oral administration. The hepatic first pass effect is
very high (30-50%). Morphine undergoes conjugation with glucuronic acid forming
3 glucuronide and 6-glucuronide.
While 3-glucuronide has no analgesic effect, the analgesic effect of 6-
glucuronide is very high.
the half life varies between 2-3 hours which is why morphine is adminisred 2-3
times a day. Indications are abdominal metastases and the pain in the lower
extremities with syringomyelia, spinal tumours and traumatic paraplegia.
26. ii. Buprenorphine is highly lipophilic, it is well absorbed and
is 40 times more potent than morphine. It has poor
bioavailability due to its high first pass metabolism which
is why it is administered parenterally, transdermal or
sublungually. Due to its high affinity for opioid receptors
it is resistant to antagonism by naloxone.
iii. Oxycodone
exhibits analgesic effect similar to morphine and is
especially used in orthopedics, i.e., following partial knee
prosthetics.
27. Opioids and anesthesia
Within the context of anesthesia, it is primarily the µ receptor that is
responsible for the opioid effects but the К receptoris also responsible
partially.
Stimulation of the µ1 receptor leads to pronounced spinal and
supraspinal analgesia but also to simultaneous respiratory depression
via the µ2 receptor.
No pure µ1 agonists have been found so far. Stimulation of the К
receptor stimulates spinal analgesia and sedating side effects via
receptors in the cortex.
fentanyl, alfentanil, sufentanil and remifentanil are pure and
selective µ agonists that are used for intravenous and balanced
anesthesia.
28. However they are not associated with liver or kidney toxicity and do not
trigger malignant hyperthermia.
They reduce CO2 sensitivity in the respiratory center leading to respiuratory
depression, resulting in hypercapnia with a significant increase in cerebral
perfusion and intracranial blood volume.
side effect of opioids is the increased tone of the bronchial musculature
resulting in increased respiratory resistance.
29. Treatment of dyspnea with opioids
Dyspnea is a common challenge during the terminal stages of many diseases.
drugs such as morphine are administered nasally or subcutaneously. The
receptor- specific opioid effects maybe competitively inhibited either
completely via pure antagonists such as naloxone or partially via mixed
agonist antagonists such as nalbuphine. Antagonists are used to eliminate the
opioid induced respiratory depression due to an absolute or relative overdose
or in the context of postoperative reversal of opioid effects.
There is risk of tachycardia and an increase in blood pressure.
its analgesic effect, however, is mainly mediated by its agonist activity at the
К receptors and its duration of action is approx. 2-3 hours.
30.
31. Opioid overdose
The triad of symptoms associated with classic opioid
overdose includes: respiratory depression with a
respiratory rate of 2-4 breaths per minute, coma and
miosis.
immediate treatment is essential in the form of assisted
ventilation and titrated administration of the antagonist
naloxone.
32.
33. Opiate withdrawal syndrome
HEROIN- opiate dependence with withdrawal symptoms develops generally
with heroin use but may also occur with prescription opioid use.
Opioid dependence is caused by the development of tolerance
pharmacodynamictolerance is based on incrased adenylyl cyclase activity.
Signs of tolerance include diminished response to the drug as well as the
shortened duration of action that is compensated by increasing the dosage.
Withdrawal symptoms include bone pain and mucle aches, fever, tachycardia,
insomnia and psychoosmotic restlessness.
Withdrawal symptoms are treated with sedating benzodiazepines with long
half life such as diazepam and sedating tricyclic antidepressants.
34.
35. Opiate replacement therapy
For many opiates addictive, replacement therapy may facilitate psychosocial
integration, reduce criminal activity for the purpose of obtaining drugs and
lower the risk of acquiring HIV and hepatitis following drug use.
In most cases, the replacement drug is methadone.
Methadone is a synthetic racemate, and only the L- form is effective. Due to
its long half-life of 24-48 hours, there is no typical ‘rush’ effect, and
therefore appropriate for replacement therapy.
Levo-alpha-acetyl methadol(LAAM) has even longer half life and does not
require administration more than 3 times per week.
36. Peripheral opioids
Loperamide: does not cross the BBB as the epithelial cells immediately pump
it back into the blood. Looperamide increases the oscillatory movement of
the gastrointestinal muscles and inhibits GI propulsion. It may reduce the loss
of enteral fluids. Loperamide is indicated as a temporary treatment for
traveller’s diarrhoea, caused by either a viral or bacterial infection.
Racecadotril: is approved for the treatment of diarrhoea in newborns, infants
and toddlers. It is administered orally and inhibits the breakdown of
enkephalins, this reducing the secretion of water and sodium in the intestinal
epithelium.
37. References
Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem.
2004;73:953-90. [PubMed]
Wolff K, Rostami-Hodjegan A, Shires S, Hay AW, Feely M, Calvert R, Raistrick
D, Tucker GT. The pharmacokinetics of methadone in healthy subjects and
opiate users. Br J Clin Pharmacol. 1997 Oct;44(4):325-34. [PMC free article]
[PubMed]
Walley AY, Xuan Z, Hackman HH, Quinn E, Doe-Simkins M, Sorensen-Alawad A,
Ruiz S, Ozonoff A. Opioid overdose rates and implementation of overdose
education and nasal naloxone distribution in Massachusetts: interrupted time
series analysis. BMJ. 2013 Jan 30;346:f174.
