Drugs acting on CNS

Opioid Analgesics and Antagonists

By:
Mr. Shivsharan B. Dhadde
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 antiinflammatory analgesics

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Opioid Analgesics
Opium: A dark brown, resinous material obtained from poppy (Papaver
somniferum) capsule. It 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 semisynthetic and synthetic compounds have been developed with
morphine-like, antagonistic and mixed agonistic-antagonistic properties.

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Opioid receptors
Morphine and other 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:
(mu) opioid receptors- (1 and 2)
(kappa) opioid receptors-(1 and 3)
(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 proteincoupled receptor
family
The analgesic properties of the opioids are primarily mediated by the
receptors that modulate responses to thermal, mechanical, and chemical
nociception.
The receptors in the dorsal horn also contribute to analgesia by modulating
the response to chemical and thermal nociception.

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Cellular Mechanisms of Action
All 3 types of opioid receptors (, , ) are G-protein coupled receptors
located mostly on prejunctional neurones.
Cellular Mechanisms of Action cont..

Binding of opioids to their receptors:

Decrease activation of the enzyme adenylyl cyclase and a subsequent
decrease in cAMP levels in the neuronal cell.
Decrease calcium entry to neuronal cells by decreasing the phosphorylation
of the voltage operating calcium channels.
Leads to potassium efflux and the resultant hyperpolarization limits the
entry of calcium to the neuronal cell by increasing the negative charge of
the membrane to levels at which these calcium channels fail to activate.

The net result of the cellular decrease in calcium is a decrease in the release of
neurotransmitter resulting in blockage of nociceptive transmission.
Actions ascribed to different types of opioid receptors

Classification of opioids
Natural opium alkaloids:
Eg.: Morphine, Codeine
Semisynthetic opiates:
Eg.: Diacetylmorphine (Heroin), Pholcodeine.
Synthetic opioids:
Eg.: Pethidine (Meperidine), Fentanyl, Methadone,
Dextropropoxyphene, Tramadol.
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 brains perception of pain.

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 center 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.
Pharmacological actions conti..........

Miosis: The pinpoint pupil is characteristic of morphine use results from

stimulation of and 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.

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.
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.
Other effects
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.
Hormonal actions: Morphine increases growth hormone release and enhances
prolactin secretion. It increases antidiuretic hormone and leads to urinary
retention.
Labor: Morphine may prolong the second stage of labor by transiently
decreasing the strength, duration, and frequency of uterine contractions.
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 bloodbrain 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-nave 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.
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 0.40.8 mg i.v. repeated every 23 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. Injection should be
repeated every 14 hours later on, according to the response. Nalorphine is no longer
used.
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 arelacrimation, 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.
Elderly male: chances of urinary retention are high.
Hypothyroidism, liver and kidney disease patients are more sensitive to morphine.
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.
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.
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 (23 hours).
3. It does not effectively suppress cough.
4. Spasmodic action on smooth muscles is less markedmiosis, 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.
6. Tachycardia (due to antimuscarinic action) occurs instead of
bradycardia.
7. It causes less histamine release and is safer in asthmatics.
8. It has local anaesthetic action: corneal anaesthesia is seen after
systemic doses.
9. It is well absorbed, oral: parenteral activity ratio is high (1/3 to 1/2).
Pethidine is nearly completely metabolized in liver. The plasma t of
pethidine is 23 hours. Acidification of urine increases excretion of
unchanged pethidine.
Side effects: These are similar to morphine except those mentioned above.
Some atropinic effects (dry mouth, blurred vision, tachycardia) may be
noted in addition.
Use
Pethidine is primarily used as an analgesic (substitute of morphine) and in
preanaesthetic medication, but not for cough or diarrhoea.
It has also been used to control shivering during recovery from anaesthesia or
that attending i.v. infusions.
USES (Of Morphine and its congeners).
As analgesic: Opioid analgesics are indicated in severe pain of any type.
However, they only provide symptomatic relief without affecting the cause.
Preanaesthetic medication: Morphine and pethidine are used in few selected
patients
Balanced anaesthesia and surgical analgesia: Fentanyl, morphine, pethidine,
alfentanil or sufentanil are an important component of anaesthetic
techniques
Relief of anxiety and apprehension: Especially in myocardial infarction,
internal bleeding (haematemesis, threatened abortion, etc.)
Cough: Codeine or its substitutes are widely used for suppressing dry,
irritating cough
Diarrhoea: The constipating action of codeine has been used to check
diarrhoea and to increase the consistency of stools in colostomy.
COMPLEX ACTION OPIOIDS AND OPIOID ANTAGONISTS
1. Agonist-antagonists ( analgesics)
Ex. Nalorphine, Pentazocine, Butorphanol
2. Partial/weak agonist + antagonist
Ex: Buprenorphine
3. Pure antagonists
Ex: Naloxone, Naltrexone, Nalmefene

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, mixed agonistantagonists show
agonist activity and are used to relieve pain. In the patient with opioid
dependence, the agonistantagonist drugs may show primarily blocking effects
Partial agonists bind to the opioid receptor, but have less intrinsic activity than
full agonists. There is a ceiling to the pharmacologic effects of these agents.
PURE OPIOID 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 agonist, and precipitate the

symptoms of opioid withdrawal.

Naloxone
Naloxone 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 is a competitive antagonist at , , and receptors, with a 10-fold

higher affinity for than for receptors.

There is little to no clinical effect seen with oral naloxone, but, upon IV
administration, opioid antagonism occurs, and the patient experiences
withdrawal.
Naltrexone
Naltrexone has actions similar to those of naloxone.

It has a longer duration of action than naloxone, and 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.

ENDOGENOUS OPIOID PEPTIDES
In the mid 1970s, with herculean efforts, a number of peptides having
morphine-like actions were isolated from mammalian brain, pituitary,
spinal cord and g.i.t.

These are active in very small amounts, their actions are blocked by
naloxone, and they bind with high affinity to the opioid receptors.

There are 3 distinct families of opioid peptides.

Each is derived from a specific large precursor polypeptide.

1. Endorphins:
-endorphin (-END) having 31 amino acids is the most important of
the endorphins.
It is derived from Pro-opiomelanocortin (POMC) which also gives rise
to -MSH, ACTH and two lipotropins. -END is primarily agonist, but
also has action.
2. Enkephalins
Methionine-enkephalin (met- ENK) and leucine-enkephalin (leu-ENK) are
the most important.

Both are pentapeptides. The large precursor peptide proenkephalin has 4

met-ENK and 1 leu-ENK residues.

The two ENKs have a slightly different spectrum of activity; while met-
ENK has equal affinity for and sites, leu-ENK prefers receptors.

3. Dynorphins
Dynorphin A and B (DYN-A, DYN-B) are 817 amino acid peptides derived
from prodynorphin which contains 3 leu-ENK residues also.

DYNs are more potent on receptors, but also activate and receptors.
The opioid peptides constitute an endogenous opioid system which
normally modulates pain perception, mood, hedonic (pleasure related)
and motor behaviour, emesis, pituitary hormone release and g.i.t.
motility, etc.