Drugs acting on CNS

Opioid Analgesics and

Antagonists

Dr. Muhammad Sarfraz

College of Pharmacy Al-Ain University
Al Ain, UAE.
Course Title: Pharmacology 3
Course Code: 0203483
Credit Hours: 3 CH
Pre -requisite: 0203382
Co -requisite: None
Academic Year: 2023-2024
Tests & Evaluations :

• Quiz 1 10%
• Midterm exam 20%
• Quiz 2 10%
• Lab Assessment 20%
• Final exam 40%

Teaching Methods
1) Lectures
3) Case Studies
 Textbook:

• Lippincott Illustrated
Reviews: Pharmacology
• Karen Whalen
• 8th edition, Oct 2022
• ISBN 10: 1975170555
 Textbook:

• Katzung's Basic and Clinical

Pharmacology.
• Author(s): by Todd W
Vanderah
• Year: 2023
• Edition : 16 th
• ISBN: 1260463303
• Nov 2023
• Publisher: McGraw Hill
Education.
 Introduction
• Algesia (pain) is an ill-defined, unpleasant sensation, usually evoked by
an external or internal noxious stimulus.
• Pain is a warning signal, primarily protective in nature, but causes
discomfort and suffering; may even be unbearable and incapacitating.

• Analgesic: A drug that selectively relieves pain by acting in the CNS or

on peripheral pain mechanisms, without significantly altering
consciousness.

• Analgesics relieve pain as a symptom, without affecting its cause. They

are used when the noxious stimulus (evoking the pain) cannot be
removed or as adjuvants to more etiological approach to pain.
Analgesics are divided into two groups, viz.
a)Opioid/narcotic/morphine-like
analgesics.
b)Nonopioid/non-narcotic/aspirin-like/antipyretic
or antii-nflammatory analgesics
 Opioid Analgesics
 The term opioid refers to all compounds related to
“opium” i.e.; natural product derived from “poppy”.
• Opium is obtained from the poppy, Papaver somniferum
and P album.
• After incision, the poppy seed pod exudes a white
substance that turns into a brown gum that is crude
opium
• Opiates are drugs derived from opium and include the
natural products and many semi- synthetic derivatives.
 Opioid analgesics are also known as “NARCOTICS”.
Opioid Analgesics
• Opium contains two types of alkaloids.
Phenanthrene derivatives
• Morphine (10% in opium)
• Codeine (0.5% in opium)
• Thebaine (0.2% in opium)-Nonanalgesic
Benzoisoquinoline derivatives
• Papaverine (1%)-Nonanalgesic
• Noscapine (6%)- Nonanalgesic
A large number of semi-synthetic and synthetic compounds
have been developed with morphine-like, antagonistic and
mixed agonistic-antagonistic properties.
Opioid Analgesics
• Opioids are a class of central acting analgesics that
provide powerful dose dependent relief of moderate
to severe pain.
• They include compounds having no cardiac or
hepato-renal toxic effects and are approved for
various routes of administration.
 Endogenous Opioid Peptides
• Endogenous opioid peptides are small molecules that
are naturally produced in the central nervous system
(CNS) and in various glands throughout the body,
such as the pituitary and adrenal glands.
• These peptides produce the same effects as the
chemicals known as classic alkaloid opiates, which
include morphine and heroin.
• Endogenous opioid peptides function both as
hormones and as neuromodulators.
 Endogenous Opioid Peptides
• Endogenous opioid peptides that serve as
neuromodulators are produced and secreted by
nerve cells (i.e., neurons) and act in the brain and
spinal cord to modulate the actions of other
neurotransmitters.
• Through these two mechanisms, endogenous
opioid peptides produce many effects, ranging from
preventing diarrhea to inducing euphoria and pain
relief (i.e., analgesia).
 FAMILIES OF ENDOGENOUS
PEPTIDES
• Three families of endogenous opioid
peptides have been described in detail:
1-endorphins,
2-pentapeptide enkephalins methionine-
enkephalin (met-enkephalin) and
leucineenkephalin (leu-enkephalin),
3-dynorphins.
 Opioid receptors Activity
• Opioids exert their actions by interacting with opioid receptors present
on neurones in the CNS and in peripheral tissues.

• Opioid receptors divided into three types:

▫ μ (mu) opioid receptors- (μ1 and μ2)
▫ κ (kappa) opioid receptors-(κ1 and κ3)
▫ δ (delta) opioid receptors

• Each has a specific pharmacological profile and pattern of anatomical

distribution in the brain, spinal cord and peripheral tissues.

• All three opioid receptors are members of the G protein–coupled

receptor family
 “OPIOIDS RECEPTORS”
These receptors are found in CNS, GIT and to a
lesser degree in peripheral tissues.
Mechanism of Action of Opioid Peptides
• Once released from the neurons, opioid peptides act through
opioid receptors on their target neurons to transmit
messages that primarily inhibit pain perception.
• In addition, opioid peptides can induce the following effects:
• • Decrease respiration
• • Stimulate or depress cardiovascular functioning, depending
on the brain area where the opioid peptides act
• • Decrease the movement (i.e., motility) of the muscles of the
gastrointestinal (GI) tract, thereby slowing down the food’s
transit through the GI tract
• • Decrease susceptibility to seizures
• Induce euphoria
 Cellular Mechanisms of Action
Binding of opioids to their receptors:
• Opioids have actions at two sites, the presynaptic nerve terminal and the
postsynaptic neuron.
• All opioid receptors are G protein-coupled receptors. Their stimulation
inhibits adenylyl cyclase resulting in decrease intra cellular cAMP.
• They inhibit opening of Ca+ channels which in turns decreases the
release of neurotransmission and thus relief pain
• They also facilitate the opening of K+ channels, causing efflux of K+,
leading to hyper polarization.
• In addition,. Various neurotransmitters include Dopamine, glutamate,
GABA ,NA, 5HT and substance P are involved in transmission of pain
impulses.

The net result of the cellular decrease in calcium is a decrease in the

release of neurotransmitter resulting in blockage of nociceptive
transmission.
Cellular
Mechanisms
of Action
Classification of Opioids

Origin of opioids: natural, semisynthetic, or synthetic.

 THERAPEUTIC CLASSIFICATION OF OPIOID
• Opioid drugs include Strong agonists, Moderate agonists & antagonists.

Summary of opioid analgesics and antagonists

with common trade names. * = Contains
acetaminophen.
MORPHINE
Pharmacological actions:
Analgesia: Morphine and other opioids
cause analgesia and relieve pain both
by raising the pain threshold at the
spinal cord level and, more
importantly, by altering the brain’s
perception of pain.
The maximum analgesic activity shown
by the opioids agonist is shown in the
figure:

A comparison of opioid agonist efficacy

Euphoria: Morphine produces a powerful sense of contentment and well-being.
Euphoria may be caused by disinhibition of the dopamine-containing neurons of the
ventral tegmental area.

Respiration: Morphine causes respiratory depression by reduction of the sensitivity of

respiratory centre neurons to CO2. Respiratory depression is the most common cause of
death in acute opioid overdoses.

Depression of cough reflex: Both morphine and codeine have antitussive properties.
The receptors involved in the antitussive action appear to be different from those
involved in analgesia.

Miosis: The pinpoint pupil is characteristic of morphine use results from stimulation of
μ and κ receptors. There is little tolerance to the effect, and all morphine abusers
demonstrate pinpoint pupils. [Note: This is important diagnostically, because many
other causes of coma and respiratory depression produce dilation of the pupil.

Emesis: Morphine directly stimulates the chemoreceptor trigger zone

(CTZ) in the area postrema that causes vomiting.
Pharmacological actions conti..........
GI tract: Morphine and most other opioids produce some degree of
constipation by increasing sphincter tone and decreasing gastric motility.
Morphine can also increase biliary tract pressure due to contraction of the
gallbladder and constriction of the biliary sphincter.

Labor: Morphine may prolong the second stage of labor by transiently

decreasing the strength, duration, and frequency of uterine contractions.

Histamine release: Morphine releases histamine from mast cells causing

urticaria, sweating, and vasodilation. Because it can cause
bronchoconstriction, morphine should be used with caution in patients with
asthma.
Cardiovascular: Morphine has no major effects on the BP or heart rate at
lower dosages. With large doses, hypotension and bradycardia may occur.
Because of respiratory depression and CO2 retention, cerebral vessels dilate
and increase CSF pressure. Therefore, morphine is usually contraindicated
in individuals with head trauma or severe brain injury.
Hormonal actions: Prolonged use of morphine may lead to opioid-
induced androgen deficiency due to suppression of the hypothalamic–
pituitary–gonadal axis (HPA). This results in decreased production of sex
hormones, especially testosterone, resulting in many clinical symptoms.

Clinical symptoms associated with

opioid-induced androgen deficiency
(OPIAD)
Pharmacokinetics
Administration:
• Because significant first-pass metabolism of morphine occurs in the liver,
intramuscular, subcutaneous, and IV injections produce the most reliable
responses.
• Absorption of morphine from the GI tract after oral absorption is slow and
erratic. When used orally, morphine is commonly administered in an
extended-release form to provide more consistent plasma levels.

Distribution:
• Morphine rapidly enters all body tissues, Including the fetuses of pregnant
women. It should not be used for analgesia during labor.
• Infants born to addicted mothers show physical dependence on opioids and
exhibit withdrawal symptoms if opioids are not administered.
• Only a small percentage of morphine crosses the blood–brain barrier. In
contrast, the more lipid-soluble opioids, such as fentanyl and methadone,
readily penetrate into the CNS.
Fate:
• Morphine is conjugated with glucuronic acid in the liver to two main
metabolites. Morphine-6-glucuronide is a very potent analgesic, whereas
morphine-3-glucuronide does not have analgesic activity.
• The conjugates are excreted primarily in urine, with small quantities
appearing in bile.
• The duration of action of morphine is 4 to 5 hours when administered
systemically to morphine-naïve individuals, but considerably longer when
injected epidurally because the low lipophilicity prevents redistribution from
the epidural space.
Adverse effects:
Side effects:
Sedation, mental clouding,
lethargy and vomiting is
occasional in recumbent patient;
constipation is common.
Respiratory depression, blurring
of vision, urinary retention
(especially in elderly male) are
other side effects. BP may fall,
especially in hypovolaemic
patient and if he/she walks
about.

Adverse effects commonly observed in

individuals treated with opioids
Idiosyncrasy and allergy :
Allergy is uncommon and anaphylactoid reaction is rare. Urticaria,
itch, swelling of lips are the manifestations. A local reaction at
injection site may occur due to histamine release.
Elevation of intracranial pressure, particularly in head injury, can be
serious.
Morphine should be used with caution in patients with asthma, liver
disease, or renal dysfunction.
Acute morphine poisoning
• In the non-tolerant adult, 50 mg of morphine i.m. produces serious toxicity.
The human lethal dose is estimated to be about 250 mg.
• Manifestations are stupor or coma, flaccidity, shallow and occasional
breathing, cyanosis, pinpoint pupil, fall in BP and shock; convulsions may be
seen in few, pulmonary edema occurs at terminal stages, death is due to
respiratory failure.
Treatment:
Consists of respiratory support and maintenance of BP (i.v. fluids,
vasoconstrictors). Gastric lavage should be done with pot. permanganate to
remove unabsorbed drug. Lavage is indicated even when morphine has been
injected.
Specific antidote:
Naloxone 0.4–0.8 mg i.v. repeated every 2–3 min till respiration picks up, is
the preferred specific antagonist because it does not have any agonistic action
and does not per se depress respiration. It has a short duration of action.
Tolerance and physical dependence:
• Repeated morphine use produces tolerance to the respiratory
depressant, analgesic, euphoric, and sedative effects of morphine.

• However, tolerance usually does not develop to the pupil-constricting

and constipating effects of the drug.

• Physical and psychological dependence can occur with morphine and

with some of the other agonists.
Morphine Withdrawal Syndrome
• Withdrawal produces a series of autonomic, motor, and psychological
responses that incapacitate the individual and cause serious symptoms.

• Withdrawal of morphine is associated with marked drug-seeking

behaviour. Physical manifestations are—lacrimation, sweating, anxiety,
fear, restlessness, mydriasis, tremor, insomnia, abdominal colic,
diarrhoea, dehydration, rise in BP, palpitation and rapid weight loss.
 Morphine Withdrawal Syndrome

Treatment: consists of withdrawal of morphine and substitution with oral methadone

(long-acting, orally effective) followed by gradual withdrawal of methadone. However,
relapse rate among postaddicts is high. Long-term methadone maintenance and other
techniques using agonist-antagonistic drugs are also employed.
 PRECAUTIONS AND CONTRAINDICATIONS
• Infants and the elderly are more susceptible to the respiratory depressant action
of morphine.
• It is dangerous in patients with respiratory insufficiency, sudden deaths have
occurred.
• Bronchial asthma: morphine can precipitate an attack by its histamine releasing
action.
• Head injury: morphine is contraindicated in patients with head injury. Reasons
are—
(a) By retaining CO2, it increases intracranial tension which will add to that
caused by head injury itself.
(b) Even therapeutic doses can cause marked respiratory depression in these
patients.
(c) Vomiting, miosis and altered mentation produced by morphine interfere with
assessment of progress in head injury cases.
• Hypotensive states and hypovolaemia exaggerate fall in BP due to morphine.
• Undiagnosed acute abdominal pain: morphine can aggravate certain conditions,
e.g. biliary colic, pancreatitis. Inflamed appendix may rupture.
 Codeine
• Codeine is a naturally occurring opioid that is a weak analgesic
compared to morphine.

• It should be used only for mild to moderate pain. The analgesic actions
of codeine are derived from its conversion to morphine by the CYP450
2D6 enzyme system.

• Drug interactions associated with the CYP450 2D6 enzyme system may
alter the efficacy of codeine or potentially lead to toxicity.

• Codeine is commonly used in combination with acetaminophen for

management of pain.

• Codeine exhibits good antitussive activity at doses that do not cause

analgesia.
 Oxycodone and oxymorphone
• Oxycodone is a semisynthetic opioid with agonistic properties on
mu, kappa, and delta-type opioid receptors, with the
strongest affinity being for mu-type receptors.
• Moa: As with other opioids, oxycodone causes hyperpolarization and
reduced excitability of neurons in the central nervous system (CNS).
This signal cascade leads to a consequent inhibition of the nociceptive
neurotransmitters acetylcholine, dopamine, GABA, noradrenaline, and
substance P.
• Oxycodone is metabolized by the hepatic enzymes CYP3A4 and
CYP2D6, producing the metabolites noroxycodone and oxymorphone,
respectively
• The plasma half-life is 3 to 5 hours, and stable plasma levels are
reached within 24 to 36 hours.
• The immediate-release formulation of oxycodone is FDA approved for
the management of acute or chronic moderate to severe pain.
Heroin(Diamorphine, Diacetylmorphine)
• It is about 3 times more potent than morphine; more lipid
soluble: enters brain more rapidly but duration of action is
similar.

• It is considered to be more euphorient (especially on i.v.

injection) and highly addicting. Because of its high potency, it
has been favoured in illicit drug trafficking.

• The sedative, emetic and hypotensive actions are said to be less

prominent.

• However, it has no outstanding therapeutic advantage over

morphine and has been banned in most countries except U.K.
 Fentanyl
• Fentanyl stimulates mu-opioid receptors in the central
nervous system (CNS), altering the body's response to pain
• a powerful synthetic opioid that is similar to morphine but is
50 to 100 times more potent,
• The drug is highly lipophilic and has a rapid onset and short
duration of action (15 to 30 minutes).
• It is usually administered IV, epidurally, or intrathecally.
• Fentanyl is combined with local anesthetics to provide
epidural analgesia for labor and postoperative pain,
• IV fentanyl is used in anesthesia for its analgesic and
sedative effects.
• An oral transmucosal preparation and a transdermal patch
are also available.
 Pethidine (Meperidine)
• Though chemically unrelated to morphine, it interacts with opioid
receptors and its actions are blocked by naloxone.
• Important differences in comparison to morphine are:
1. Dose to dose 1/10th in analgesic potency; however, analgesic efficacy
approaches near to morphine and is greater than codeine.
2. After i.m. injection, the onset of action is more rapid but duration is
shorter (2–3 hours).
3. It does not effectively suppress cough.
4. Spasmodic action on smooth muscles is less marked—miosis,
constipation and urinary retention are less prominent.
5. It is equally sedative and euphoriant, has similar abuse potential.
The degree of respiratory depression seen at equianalgesic doses is
equivalent to morphine.
 METHADONE
• Methadone is a synthetic opioid and full agonist at the μ-
opioid receptor and induces other opioid receptors..
• Methadone is also a non-competitive antagonist to the N-
methyl-d-aspartate (NMDA) receptor, possibly further
adding to its benefits for cancer and neuropathic pain.
• Methadone is available as a lipophilic hydrochloride salt in oral,
IM, IV, subcutaneous, epidural, and intrathecal formulations.
• Methadone is a useful agent for opioid withdrawal symptoms
such as tachycardia, diaphoresis, nausea, vomiting, diarrhea,
etc.
• Methadone has high oral bioavailability, with plasma levels
measurable after 30 minutes.
• Methadone prescriptions are for detoxification and
maintenance therapy
Selected
clinical uses
of opioids
 Mixed agonist–antagonists
• Nalbuphine and butorphanol
• Nalbuphine is a strong κ-receptor agonist and a μ-receptor antagonist; it
is given parenterally.
• Buprenorphine is a potent and long-acting phenanthrene derivative that
is a partial μ-receptor agonist and a κ–receptor antagonist.
Administration by the sublingual route is preferred to avoid significant
first-pass effect. Its long duration of action is due to its slow dissociation
from μ receptors.
• Uses: detoxification and maintenance of heroin abusers. Buprenorphine
was approved by the FDA in 2002 for the management of opioid
dependence.
• Moreover, buprenorphine is also available combined with a pure μ-opioid
antagonist (Suboxone) to help prevent its diversion for illicit intravenous
abuse.
• A slow-release transdermal patch preparation that releases drug over a
1-week period is also available.
• 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.
 Buprenorphine
• a synthetic opioid, treats pain and opioid addiction.
• It is a synthetic analog of thebaine, an alkaloid compound derived
from the poppy flower.
• It is a schedule III drug, which means that it has some potential for
moderate or low physical dependence or high psychological
dependence
• It is an agent used in agonist substitution treatment, which is a
process for treating addiction by using a substance (such as
buprenorphine or methadone) to substitute for a stronger full
agonist opioid (such as heroin).
• The prescriber then tapers down the substitute, and the patient
withdraws from the opiate addiction with minimal discomfort.
• Buprenorphine substitute treatment allows the patient to focus on
therapy instead of uncomfortable withdrawals. It is an effective
option to treat opioid dependence, reduce cravings, and
improve the quality of life for patients undergoing addiction
treatment.
• MOA: Buprenorphine is a partial agonist at the mu receptor, meaning
that it only partially activates opiate receptors. It is also a weak kappa
receptor antagonist and delta receptor agonist. It is a potent
analgesic that acts on the central nervous system (CNS).
• Oral, buccal film and sublingual tablets, intravenous (IV) or
intramuscular (IM) injections.
• Buprenorphine is indicated for long-lasting painful conditions
requiring an opioid analgesic, e.g. cancer pain
• Naloxone is added to buprenorphine to reduce its abuse potential
when injected.
• Sublingual buprenorphine preparations are helpful in the
management of opioid dependence (such as heroin, oxycodone,
hydrocodone, morphine).
• Adverse Effects
• central nervous system depression, hypotension, QT prolongation,
miosis, nausea.
 Pentazocine
• Pentazocine has weak antagonist or partial agonist activity to the µ
type opiate receptors, with full agonist activity at the ĸ opioid receptor.
• Pentazocine is a controlled substance and is classified as a Schedule
IV drug, indicating that it has medical usefulness and a mild
potential for physical and psychological dependency and abuse.
• Pentazocine promotes analgesia by activating receptors in the
spinal cord, and it is used to relieve moderate pain
• Currently, it is only available in tablet form in combination with either
acetaminophen or naloxone.
• Pentazocine is indicated for postoperative and moderately
severe pain in burns, trauma, fracture, cancer, etc.
• High doses increase blood pressure and can cause
hallucinations, nightmares, dysphoria, tachycardia, and
dizziness.
 OPIOID ANTAGONISTS
• Naloxone is a pure, competitive opioid antagonist with a high
affinity for the mu-opioid receptor, allowing for 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.
• It has a half-life of 30 to 120 minutes, depending on the route
of administration, with IV being the fastest.
• A small initial dose, usually 0.04 mg to 0.1 mg IV, is
recommended in opioid- dependent patients with symptoms
of opioid overdose to avoid opioid withdrawal symptoms.
• Larger initial dosing, such as 0.4 mg IV, is recommended in
patients without a known history of opioid dependency.
• Naloxone is a competitive antagonist at μ, κ, and δ
receptors, with a 10-fold higher affinity for μ than for κ
receptors.
• Naloxone [nal-OX-own] is used to reverse the
coma and respiratory depression of opioid
overdose.
• Onset: 2 min (IV); 2-5 min (IM/SC)
• Adverse Effects
• Naloxone has few side effects. The most common are
those of acute withdrawal from opioids, such as
anxiety, nausea, diarrhea, abdominal pain, and
rhinorrhea.
• In rare cases, the use of naloxone can precipitate
noncardiogenic pulmonary edema.
 Naltrexone
• Naltrexone is an opioid antagonist used to treat alcohol use disorder and
opioid dependence.
• Naltrexone (and its active metabolite 6-beta-naltrexol) is pharmacologically
effective against alcohol and opioids by blocking the mu-opioid receptor.
• Naltrexone is also a weaker antagonist of the kappa and delta-opioid
receptors.
• Naltrexone blocks the effect of opioids and prevents opioid intoxication
and physiologic dependence on opioid users..
• Naltrexone absorption is almost complete after oral administration, but it has
an extensive first-pass effect.
• After oral administration, the half-life is 4 hours, and following an
intramuscular injection (IM), the half-life is 5 to 10 days.
• excretion is primarily through urine.
• Onset: 15-30 min, Duration: 24 hr
• Naltrexone can lead to hepatotoxicity.
• Injection site reaction,Nausea, Headache ,Decreased appetite, Insomnia
, Vomiting
Tramadol
Other Analgesics
•Tramadol [TRA-ma-dole] is a centrally acting analgesic that binds
to the μ opioid receptor.
•In addition, it weakly inhibits reuptake of norepinephrine and
serotonin. It is used to manage moderate to moderately severe
pain.
•The liver enzyme, CYP2D6, converts tramadol to its active metabolite
M1, which has a stronger affinity for the mu receptor compared to the
inactive form.
•There are two different formulations of tramadol: extended-release
and immediate release.
•Half-life: Six hours
•Time for the drug to reach peak concentration: Extended Release: 12
hours
•The most prevalent side effects are nausea, dizziness,
constipation,respiratory depression.
Drug Interactions
 54

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