Narcotic Analgesic

Submitted to:

M Borhan Uddin, Faculty, NSU

2

NAME ID1. 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.

Introduction

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.

Introduction

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

(heroin) , which may be considered to be the first

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

pathway.

How Does Narcotic Analgesic Works???

OPIOID RECEPTORS

• 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

homogenates.

• 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

suppressants.

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

receptor.

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

MORPHINE DERIVATIVES

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 R’’R’

R Anelgesia vs.

Morphine

Me Heterocodeine

Et 6-Ethylmorphine

Acetyl 6-Acetylmorphine

5 X

Greater

4 X greater

R’ R’’ Anelgesia vs.

Morphine

H OH

H H

Ketone Ketone

Increased

Or

Similar

Fig : Effect of loss of alcoholic group on analgesic activity

The results in Fig. show that masking or the complete loss of the alcohol groupdoes not decrease analgesic activity and, in fact, often has the opposite effect

Ac

Ac

Heroin has two polar groups which are masked and is therefore the most efficientcompound 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 itsremoval 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

analgesic activity.

PRECAUTION OF MORPHINE

ADMINISTRATION

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 oral/anal ingestion.

For example:

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.

Precaution: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 tachycardia.

D. Convulsions:

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

Toxicity:

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.

For example:

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 Diamorphine (Heroin)

• 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

• Septicemia

• Respiratory depression

• Seizures

• Overdose

• Death

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 DEPENDENCE

Constricted pupils (or dilated pupils with meperidine)

Euphoria

Apathy

Dysphoria

Drowsiness

Loss of consciousness

Coma

Psychomotor agitation or retardation

Decreased respiration

Decreased heart rate

Pulmonary edema

Impaired social judgment

Slurred speech

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

• Rhinorrhea

• Epiphora/lacrimation

• Piloerection

• Nausea

• Vomiting

• Diarrhea

• Yawning

• Muscle cramps

• Restlessness

• Elevated vital signs

Drug Withdrawal Effect

MANAGEMENT OF OPIOID ABUSE AND DEPENDENCE

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

*References

* The Pharmacological Basis of Therapeutics, Goodman & Gillman 12th ed Ch 18 Pg 481

* Foy’s Principles of Medicinal Chemistry 6th ed Pg 652

* http://en.wikipedia.org/wiki/Morphine

* nawrot.psych.ndsu.nodak.edu/courses/.../morphine/Page2WP.htm

* www.rxmed.com/.../MORPHINE%20SULFATE%20INJECTION%20BP.html

* depression.about.com/od/glossaryt/g/toxicity.htm

* medical-dictionary.thefreedictionary.com/morphine+poisoning

* www.drugbank.ca/drugs/DB00295

* http://www.answers.com/Q/What_is_the_antidote_for_morphine

* www.optionsbehavioralhealthsystem.com/.../heroin/effects-signs-symptoms

* http://www.drugs.com/drug-class/narcotic-analgesics.html

SINCERELY,

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