This is a presentation on Narcotic analgesic. I tried not to elaborate details and make it as precise as possible.
Published on: Mar 3, 2016
Transcripts - Narcotic analgesic
M Borhan Uddin, Faculty, NSU
1. Liyad Salem 111 0901 046
2. Istiaque Hasan 103 0638 546
3. Tamnia Islam 113 0521 046
4. Farhana Jesmin 113 0620 046
5. Taposi Alija Amrin Khan 122 1138 046
Agents that decrease pain are referred to as analgesics, pain
relieving agents also are called Anti-nociceptives. A number of
classes of drugs are used to relieve pain. For example-
(1) NSAID are useful for mild to moderate pain,
(2) Local anesthetics inhibit pain transmission by inhibiting ion of
voltage- regulated sodium channels. These agents often are highly
toxic when used in concentrations sufficient to relieve chronic or
acute pain in ambulatory patients. Severe acute or chronic pain
generally is treated most effectively with Narcotic Analgesic. So,
Morphine and its derivatives are unique among all other analgesics
in reducing pain.
Morphine is an Opioid analgesic drug or known as Narcotic
Analgesic, and the main psychoactive chemical in Opium. In clinical
medicine, morphine is regarded as the gold standard of analgesics
used to relieve intense pain. Like other opioids morphine acts directly
on the CNS to relieve pain.
The Juice or latex from the unripe seed of the Poppy
is among the oldest recorded medications used by
humans. Theophrastus describe the use of Opium as
medicine around 200 BC. However, the initial use of
opium was as tonic or being smoked till Pharmacist
Surturner isolated an alkaloid from Opium in 1803 and
named it as Morphine, after Morpheus, the Greek god
of dreams. So, Morphine was among the first
compounds to undergo structure modification. Ethyl-
morphine (the 3-ethyl ether of morphine) was
introduced as a medicine in 1898. Diacetylmorphine
History of Narcotic Analgesic
Why Do We Use Narcotics ?
How Does Narcotic Analgesic Works ?
Morphine and its analogues, and some synthetic derivatives are classed as
narcotics analgesics. Narcotic analgesics are used to relieve acute and chronic,
severe pain. Some narcotics are more potent than others. They also have the
tendency to cause tolerance and dependence.
Narcotic Analgesic exert their major effects by interacting stereo-specifically with
opioid receptors, which are present in the central and peripheral nervous system and
other anatomic structures, such as the gastrointestinal (GI) tract and the urinary bladder.
There are three types of opioid receptors, which are all G-protein linked and either
facilitate opening of potassium channels (causing hyperpolarization) or inhibit calcium
channel opening (so inhibits release of excitatory neurotransmitters such as substance
P). Overall, narcotic analgesics reduce neuronal excitability in the pain carrying
How Does Narcotic Analgesic Works???
• By the mid-1960s, it had become apparent from medicinal chemistry
and pharmacologic studies that opiate drugs were likely to exert their
actions at specific receptor sites, and that there were likely to be
multiple such sites. Early studies had indicated that opiates appeared to
accumulate in the brain. The receptors were first identified as specific
molecules through the use of binding studies, in which opiates that had
been labeled with radioisotopes were found to bind to brain membrane
• Opioids produce effects on neurons by acting on receptors located on
neuronal cell membranes. Three major types of opioid receptor- μ, κ, δ
(mu, kappa, and delta) these receptors results in the inhibition of
voltage-gated Ca2+ channels and/or the opening of K+ channels, which
results in hyperpolarization and less neuronal excitability
RECEPTOR BINDING OF MORPHINE
Morphine exerts a narcotic action
manifested by analgesia,
drowsiness, changes in mood, and
mental clouding. The major medical
action of morphine sought in the
CNS is analgesia.
Opiates suppress the "cough center"
which is also located in the
brainstem, the medulla. Such an
action is thought to underlie the use
of opiate narcotics as cough
RECEPTOR BINDING OF MORPHINE
Morphine activates analgesic receptors in the CNS. Which leads to a reduction in the
transmission of pain signal to the brain. There are 3 main types of analgesic or o opioid receptor
activated by morphine. Called the mu, kappa, delta receptors. Which are g-protein coupled
Morphine acts a agonist at all three receptors and activation leads to :
Opening of potassium ion channel
Closing of calcium ion channels Reduces the pain signal
Inhibition of Neurotransmitter release
Morphine has high affinity for mu receptor. Activation of the mu receptor results in sedation,
which is the strongest analgesic effect. But activation of this receptor also leads to depression,
euphoria, and addiction.
RECEPTOR BINDING OF MORPHINE
Antagonist: When an allyl or a cyclopropylmethylene group
attached to nitrogen. Naloxone, Naltraxon or nalorphine is
produced, which are antagonist of morphine.
Morphine and its Structure
A rigid pentacyclic structure consisting of a benzene ring (A), two partially
unsaturated cyclohexane rings (B and C), a piperidine ring (D) and
a tetrahydrofuran ring (E). Rings A, B and C are the phenanthrene ring system.
Two hydroxyl functional groups: a C3-phenolic OH and a C6-alcoholic OH
An ether linkage between C4 and C5,
Unsaturation between C7 and C8,
A basic, 3o-amine function at position 17,
5 centers of chirality (C5, C6, C9, C13 and C14)
Structural Modifications and SAR
The alcoholic OH
R Anelgesia vs.
4 X greater
R’ R’’ Anelgesia vs.
Fig : Effect of loss of alcoholic group on analgesic activity
The results in Fig. show that masking or the complete loss of
the alcohol group
does not decrease analgesic activity and, in fact, often has the
Heroin has two polar groups which are masked and is
therefore the most efficient
compound of the three to cross the blood-brain barrier.
Fig : Diamorphine (Heroin)
To conclude, the 6-hydroxyl group is not required for
analgesic activity and its
removal can be beneficial to analgesic activity
Morphine analogues better or worse ?
Morphine has three polar groups (phenol,
alcohol, and an amine), whereas the
analogues above have either lost the
polar alcohol group or have it masked by
an alkyl or acyl group.
They, therefore enter the brain more easily
and accumulate at the receptor sites in
greater concentrations; hence, the better
PRECAUTION OF MORPHINE
There are several ways to administer morphine into the body. Most
commonly, morphine is thought as being administered to a patient in a
controlled medical setting by intravenous injection. Other methods of
administration include smoking/inhaling, injecting, snorting, and
Morphine Sulfate Injection, BP (1 mg/mL and 2 mg/mL) .It may be
administered by s.c. or slow i.v. injection or by i.v. infusion.
A. Acute Abdominal Condition:
The administration of morphine or other opioids may obscure the
diagnosis or clinical course in patients with acute abdominal conditions.
B. Hypotensive Effect:
The administration of morphine may result in severe hypotension in the
postoperative patient or any individual whose ability to maintain blood
pressure has been compromised by a depleted blood volume or the
administration of such drugs as the phenothiazines or certain anesthetics.
C. Supraventricular Tachycardias:
Because of possible vagolytic action that may produce a significant
increase in the ventricular response rate, morphine should be used with
caution in patients with atrial flutter and other supraventricular
Morphine may aggravate pre-existing convulsions in patients
with convulsive disorders. If dosage is escalated substantially above
recommended levels because of tolerance development, convulsions
may occur in individuals without a history of convulsive disorders.
E. Other Special Risk Patients:
Morphine should be given with caution to certain patients, such
as the elderly or debilitated and those with severe impairment of
hepatic or renal function, hypothyroidism, Addison's disease,
prostatic hypertrophy or urethral stricture. It should be used with
extreme caution in patients with disorders characterized by hypoxia,
since even usual therapeutic doses of opioids may decrease
respiratory drive to the point of apnea while simultaneously
increasing airway resistance. It may have a prolonged duration and
cumulative effect in patients with kidney or liver dysfunction. In
these patients, analgesia may last for 6, 8 or even up to 24 hours
following a standard dose. Continuous infusions should be avoided.
F. Information for the Patient:
Occupational Hazards: Morphine may impair the mental and/or
physical abilities required for the performance of potentially
hazardous tasks, such as driving a car or operating machinery.
Morphine in combination with other opioid analgesics,
phenothiazines, sedative-hypnotics or alcohol has additive
depressant effects. The patient should be cautioned accordingly.
TOXICITY OF MORPHINE
It occurs when a person has accumulated too much of a drug in his bloodstream,
leading to adverse effects within the body. Drug toxicity may occur when the dose
given is too high or the liver or kidneys are unable to remove the drug from the
bloodstream, allowing it to accumulate in the body.
Toxicity of Morphine:
It adverse effect of injection or ingestion of opioids, marked by symptoms of pinpoint
pupils, drowsiness, and shallow respiration. Emergency treatment includes gastric
lavage, charcoal, and respiratory support. Naloxone is administered intravenously as
needed to arouse the patient, and IV fluid is given to support circulation.
Toxic dose of morphine:
Toxicity of LD50 = 461 mg/kg (rat, oral), 600 mg/kg (mouse, oral). Human lethal dose
by ingestion is 120-250 mg of morphine sulfate. Symptoms of overdose include cold,
clammy skin, flaccid muscles, fluid in the lungs, lowered blood pressure, "pinpoint" or
dilated pupils, sleepiness leading to stupor and coma, slowed breathing, and slow pulse
rate.As a result, it must be affected organisms Humans and other mammals.
A large overdose can cause asphyxia and death by respiratory depression if the
person does not receive medical attention immediately. Overdose treatment
includes the administration of naloxone. The latter completely reverses morphine's
effects, but precipitates immediate onset of withdrawal in opiate-addicted subjects.
Multiple doses may be needed.The minimum lethal dose is 200 mg, but in case of
hypersensitivity, 60 mg can bring sudden death. In serious drug dependency (high
tolerance), 2000–3000 mg per day can be tolerated.
Antidote of morphine:
The antidote for morphine, and most other opioids, is a medication called
naloxone, or Narcan. It blocks opioid receptors, blocking the effect of morphine,
heroin, or any other opiate medication. The effects of naloxone are short-lived,
however, and may require further dosing to keep the patient from slipping back
into a coma. If a person has taken an overdose of morphine, they are usually given
an opiate antagonist, such as Narcan. This acts very quickly in reversing the
effects of the morphine, or any other narcotic. Narcan is also sometimes used in
drug rehab; it helps the body to go through the withdrawal symptoms more
quickly. But this must be done under the supervison of a doctor on an in-patient
basis (sometimes while the patient is under general anesthesia), since sudden
withdrawal of narcotics can cause serious or even fatal reactions.
SIDE EFFECTS of
• The effects of heroin abuse will differ from person to person, depending upon the length of abuse, amount
of heroin used, the presence of other substances, and individual makeup. Severity of symptoms tend to get
worse the longer the drug is abused.
• The most common effects of heroin addiction may include:
• Liver disease
• Skin disease and abscesses around injection sites
• Infections of the valves and lining of the heart
• HIV or Hepatitis B and C
• Chronic pneumonia
• Clouded mental functioning
• Collapsed, scarred veins
• Blood clots, leading to stroke, pulmonary embolism, and heart attack
• Kidney disease
• Risks of contracting chronic illnesses
• Risks for blood-borne pathogens
• Respiratory depression
Conceptual framework of addiction
Drug addiction or substance dependence, is a chronically relapsing disorder
characterized by: (a) compulsion to seek and take the drug, (b) loss of control in
limiting intake, and (c) emergence of a negative emotional state (e.g., dysphoria,
anxiety, irritability) when access to the drug is prevented. Clinically, the
occasional but limited use of an abusable drug is distinct from escalated drug
use and the emergence of chronic drug dependence.
Risk factors of narcotic abuse and dependence
Individuals who use nonmedical
prescription opioids before 13 years of
age are more likely to become addicts
than those who initiated use at 21 years
of age or older. The odds of becoming
an addict are reduced 5% each year
after 13 years of age Additionally, it is a
commonly held view among
adolescents (41%) that prescription
drugs are "much safer" than street drugs
.This belief is undoubtedly shared with
much of the adult population and has
led to the extraordinary rise in
recreational prescription drug users.
EFFECTS OF OPIOID ABUSE AND
Constricted pupils (or dilated pupils with meperidine)
Loss of consciousness
Psychomotor agitation or retardation
Decreased heart rate
Impaired social judgment
Impaired attention and memory
Impaired occupational functioning
• A withdrawal syndrome can be precipitated in humans after even a single dose of
morphine. Physical dependence to opioids is assessed by observing the emergence
of a withdrawal syndrome following discontinuation of opioid administration or
through the administration of a competitive opioid antagonist, such as naloxone
Signs and symptoms of opioid withdrawal include:
• Dilated pupils
• Muscle cramps
• Elevated vital signs
Drug Withdrawal Effect
MANAGEMENT OF OPIOID ABUSE
Today, management of opioid dependence entails different methods to achieve different
goals, depending on the health situation and treatment history of the patient. These
treatment approaches include :
• Crisis intervention: Directed at immediate survival by reversing the potentially
lethal effects of overdose with an opioid antagonist.
• Harm reduction: Intended to reduce morbidity and mortality associated with use
of dirty needles and overdose.
• Detoxification/withdrawal: Aims to remove the opioid of abuse from the
patient's body, either through gradual taper and substitution of a long-acting opioid
or through ultra-rapid opioid detoxification.
• Maintenance treatment or opioid (agonist) replacement therapy: Aimed
at reduction/elimination of illicit opioid use and lifestyle stabilization. Maintenance
follows detoxification/withdrawal, whereby the patient is tapered from short-acting
opioids and introduced to long-acting opioid agonist, such as methadone or
buprenorphine. Patients remain on agonist therapy short-term, long-term, or
indefinitely depending on individual needs.
• Abstinence-oriented therapy: Treatment directed at cure. The patient is
tapered off of short-acting opioids during the detoxification/withdrawal process and
may be placed on an opioid antagonist with the goal of minimizing relapse.
All treatment approaches share the common goal of improving health outcomes and
reducing drug-related criminality and public
* The Pharmacological Basis of Therapeutics, Goodman & Gillman 12th ed Ch 18 Pg 481
* Foy’s Principles of Medicinal Chemistry 6th ed Pg 652