NARCOTIC ANALGESICS pdf - د. نجيب

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NARCOTIC ANALGESICS

Lecture 5

Total lectures NO. 38

Dr. Najeeb

Opioid Analgesics and Antagonists

The opioids include

1- natural opiates

2- semisynthetic alkaloids derived from the opium poppy
,3- pharmacologically similar synthetic surrogates
4- endogenous peptides

Classification

On the basis of their interaction with opioid receptors, the

Drugs are classified as

1- agonists (full or partial),

2- mixed agonist-antagonists (capable of activating one receptor

subtype and blocking another receptor subtype)

)

3- antagonists (receptor blockers) ),

Opioid antagonist A drug that blocks

some or all opioid receptor subtypes

1-Agonists

. Absorption and Distribution

Most drugs in this class are well absorbed when taken orally, but

morphine, hydromorphone, and oxymorphone undergo extensive first-
pass metabolism. In most cases, opioids can be given

parenterally, and sustained-release forms of some drugs are now

available, including morphine and oxycodone.

widely distributed to body tissues. They cross the placental barrier

and exert effects on the fetus that can result in both respiratory

depression and, with continuous exposure, physical dependence

in neonates

. Metabolism

With few exceptions, the opioids are metabolized by hepatic

enzymes, usually to inactive glucuronide conjugates, before their

elimination by the kidney. However, Codeine, oxycodone, and
hydrocodone are metabolized by

cytochrome CYP2D6, an isozyme exhibiting genotypic variability.

. Depending on the specific drug, the duration of

their analgesic effects ranges from 1–2 h (eg, fentanyl) to 6–8 h

(

eg, buprenorphine). However, long-acting formulations of some

drugs may provide analgesia for 24 h or more. The elimination half-life

of opioids increases in patients with liver disease

Remifentanil, a congener of fentanyl, is metabolized by plasma

and tissue esterases and has a very short half-life

MECHANISMS OF ACTION

Receptors

Three major opioid receptor subtypes have been

extensively characterized : μ , δ , and κ receptors

All 3 receptor subtypes appear to be involved in antinociceptive

and analgesic mechanisms at both spinal and supraspinal levels

The μ-receptor activation plays a major role in the respiratory

depressant actions of opioids and together with κ-receptor activation
slows gastrointestinal transit; κ-receptor activation also

appears to be involved in sedative actions; δ-receptor activation

may play a role in the development of tolerance

. Opioid Peptides

Opioid receptors are thought to be activated by endogenous

peptides under physiologic conditions. These peptides, which

include endorphins such as β-endorphin, enkephalins, and dynorphins,
are synthesized in the soma and are transported to the nerve

endings where they accumulate in synaptic vesicles. On release

from nerve endings, they bind to opioid receptors and can be

displaced from binding by opioid antagonists. Although it remains
unclear whether

these peptides function as classic neurotransmitters, they appear to

modulate transmission at many sites in the brain and spinal cord

and in primary afferents. Opioid peptides are also found in the

adrenal medulla and neural plexus of the gut

. Ionic Mechanisms

Opioid analgesics inhibit synaptic activity partly through direct

activation of opioid receptors and partly through release of the

endogenous opioid peptides, which are themselves inhibitory

At the postsynaptic level, activation of these

receptors can open potassium ion channels to cause membrane

hyperpolarization (inhibitory postsynaptic potentials).

At the presynaptic level, opioid receptor activation can close voltage-
gated calcium ion channels

–

resulting in the inhibition of release

of multiple neurotransmitters, including acetylcholine (

norepinephrine, serotonin, glutamate, and substance P

EFFECTS

1. Analgesia

The opioids are the most powerful drugs available for the relief

of pain. They attenuate both emotional and sensory aspects of

the pain experience.

1- Strong agonists (ie, those with the highest analgesic efficacy, full
agonists) include

morphine, methadone, meperidine, fentanyl, levorphanol, and heroin. s

2- partial agonists with mild to moderate analgesic efficacy include

Codeine, hydrocodone

and oxycodone . They are commonly available in combinations

with acetaminophen and nonsteroidal anti-inflammatory drugs

(

NSAIDs).

3- very weak agonist drugs include propoxyphene which is also

available combined with acetaminophen

3. Sedation and Euphoria

The sedation is additive with other CNS

depressants. At higher doses,

the drugs may cause mental clouding and result in a stuporous or even
a comatous state.

Some patients experience

dysphoric effects from opioid drugs.

3. Respiratory Depression

Opioid actions in the medulla lead to inhibition of the respiratory

center, with decreased response to carbon dioxide challenge. With

full agonists, respiratory depression may be seen at conventional

analgesic doses. Increased PCO2

may cause cerebrovascular dilation, resulting in increased blood flow
and increased intracranial

pressure. Opioid analgesics are relatively contraindicated in patients

with head injuries

4. Antitussive Actions

Suppression of the cough reflex by unknown mechanisms is the

basis for the clinical use of opioids as antitussives. a

5. Nausea and Vomiting

Nausea and vomiting are caused by activation of the chemoreceptor

trigger zone and are increased by ambulation

6. Gastrointestinal Effects

Constipation occurs through decreased intestinal peristalsis

which is probably mediated by effects on opioid receptors in the

enteric nervous system. This powerful action is the basis for the

clinical use of these drugs as antidiarrheal agents

7. Smooth Muscle

Opioids (with the exception of meperidine) cause contraction

of biliary tract smooth muscle, which can result in

biliary colic

or spasm,

increased ureteral and bladder sphincter tone, d

reduction in uterine tone, which may contribute to prolongation

of labor

8. Miosis

Pupillary constriction is a characteristic effect of all opioids except

meperidine, which has a muscarinic blocking action. Little on

no tolerance occurs. Miosis is blocked by the opioid antagonist

naloxone and by atropine

9. Miscellaneous

Opioid analgesics, especially morphine, can cause flushing and

pruritus through histamine release. They cause release of antidiuretic
hormone (ADH) and prolactin but may inhibit the release

of luteinizing hormone (LH). Exaggerated responses to opioid

analgesics may occur in patients with adrenal insufficiency or

10- Tolerance

Marked tolerance can develop to the just-mentioned acute

pharmacologic effects, with the exception of miosis and constipatione

Although there is cross tolerance between different opioid agonists, it is

not complete . This provides the basis for “opioid rotation,” whereby
analgesia is maintained (eg, in cancer patients) by changing from one

drug to another

11- Dependence

Physical dependence is an anticipated physiologic response to

chronic therapy with drugs in this group, particularly the strong

agonists. Physical dependence is revealed on abrupt discontinuance as

an abstinence syndrome, which includes rhinorrhea

lacrimation, chills, gooseflesh, muscle aches, diarrhea, yawning, anxiety,
and hostility. A more intense state of precipitated

withdrawal results when an opioid antagonist is administered to

a physically dependent individual

CLINICAL USES

1. Analgesia

Treatment of relatively constant moderate to severe pain is the major

indication. In the acute

setting, strong agonists are usually given parenterally. Prolonged
analgesia, with some reduction in adverse effects, can be achieved with

epidural administration of certain strong agonist drugs (eg, fentanyl

and morphine). Fentanyl has also been used by the transdermal route

providing analgesia for up to 72 h. For less severe pain and in the

chronic setting, moderate agonists are given by the oral route,

sometimes in combinations with acetaminophen or NSAIDs

2. Cough Suppression

Useful oral antitussive drugs include codeine and dextromethorphan

Large doses of

dextromethorphan may cause hallucinations, confusion, excitation

increased or decreased pupil size, nystagmus, seizures, coma, and

decreased breathing

3. Treatment of Diarrhea

Selective antidiarrheal opioids include diphenoxylate and

loperamide. They are given orally

4. Management of Acute

ulmonary Edema

Morphine (parenteral) may be useful in acute pulmonary edema

because of its hemodynamic actions; its calming effects probably

also contribute to relief of the pulmonary symptoms

5. Anesthesia

Opioids are used as preoperative medications and as intraoperative
adjunctive agents in balanced anesthesia protocols. High-dose

intravenous opioids (eg, morphine, fentanyl) are often the major

component of anesthesia for cardiac surgery

6. Opioid Dependence

Methadone, one of the longer acting opioids, is used in the management
of opioid withdrawal states and in maintenance programs

for addicts.

In withdrawal states, methadone permits a slow tapering of opioid
effect that diminishes the intensity of abstinence

symptoms. Buprenorphine (see later discussion) has an even longer

duration of action and is sometimes used in withdrawal states

In maintenance programs, the prolonged action of methadone

blocks the euphoria-inducing effects of doses of shorter acting

opioids (eg, heroin, morphine

)

TOXICITY

Nausea, constipation, respiratory depression) are predictable

In cases of overdose

A triad of pupillary constriction, comatose state, and respiratory

depression is characteristic; the latter is responsible for most

fatalities. Diagnosis of overdosage is confirmed if intravenous

injection of naloxone, an antagonist drug, results in prompt signs

of recovery. Treatment of overdose involves the use of antagonists

such as naloxone and other therapeutic measures, especially ventilatory

support

. Drug Interactions

1- additive CNS depression with ethanol, sedative-hypnotics

anesthetics, antipsychotic drugs, tricyclic antidepressants, and

antihistamines.

2- Concomitant use of certain opioids (eg, meperidine) with monoamine

oxidase inhibitors increases the incidenc of hyperpyrexic com .3-e

Meperidine has also been implicated in the serotonin syndrome when

used with selective serotonin reuptake inhibitors

2-AGONIST-ANTAGONIST DRUGS

. Analgesic Activity

The analgesic activity of mixed agonist-antagonists varies with

the individual drug but is somewhat less than that of strong

full agonists like morphine. Buprenorphine, butorphanol, and

nalbuphine afford greater analgesia than pentazocine, which is

similar to codeine in analgesic efficacy

. Receptors

Butorphanol, nalbuphine, and pentazocine are κ agonists, with

Weak μ-receptor antagonist activity. Butorphanol may act as a

partial agonist or antagonist at the μ-receptor

Buprenorphine is a μ-receptor partial agonist with weak

antagonist effects at κand δreceptors. These characteristics can

lead to decreased analgesia, or even precipitate withdrawal symptoms,
when such drugs are used in patients taking conventional

full μ-receptor agonists. Buprenorphine has a long duration of

effect binding strongly to μ receptors. Although prolonged activity of
buprenorphine may be clinically useful (eg, to suppress

withdrawal signs in dependency states), this property renders its

effects resistant to naloxone reversal, since the antagonist drug

has a short half-life. In overdose, respiratory depression caused by

nalbuphine may also be resistant to naloxone reversal. Naloxone

is included in some formulations of these agonist-antagonist drugs

to discourage abuse

. Effects

The mixed agonist-antagonist drugs often cause sedation at

analgesic doses. Dizziness, sweating, and nausea may also

occur, and anxiety, hallucinations, and nightmares are possible

adverse effects. Respiratory depression may be less intense than

with pure agonists but is not predictably reversed by naloxone

Tolerance develops with chronic use but is less than the tolerance that
develops to the pure agonists, and there is minimal

cross-tolerance. Physical dependence occurs, but the abuse

liability of mixed agonist-antagonist drugs is less than that of

the full agonists

. Miscellaneous

Tramadol is a weak μ-receptor agonist only partially antagonized

by naloxone. The analgesic activity of tramadol is mainly based

on blockade of serotonin reuptake; it is a weak norepinephrine

reuptake blocker. Tramadol is effective in treatment of moderate

pain and has been used as an adjunct to opioids in chronic pain

syndromes. The drug is relatively contraindicated in patients with

a history of seizure disorders, and there is risk of the serotonin

syndrome if it is co-administered with SSRIs. No significant effects

on cardiovascular functions or respiration have been reported

Tapentado lis a newer analgesic with strong norepinephrine

reuptake-inhibiting activity (its activity is blocked by alpha antagonists)
and only modest μ-opioid receptor affinity. It is not as

effective as oxycodone in the treatment of moderate to severe pain

but causes less gastrointestinal distress and nausea.

Tapentadol has

been implicated in the serotonin syndrome and should be used

with caution in patients with seizure disorders

3-OPIOID ANTAGONISTS

Naloxone, nalmefene, and naltrexone are pure opioid receptor

antagonists . These drugs have greater

affinity for μ receptors than for other opioid receptors. A major

clinical use of the opioid antagonists is in

1- the management of acute opioid overdose. Naloxone and nalmefene
are given

intravenously. Because naloxone has a short duration of action

(

–

h), multiple doses may be required in opioid analgesic overdose.
Nalmefene has a duration of action of 8–12 h. Naltrexone

has a long elimination half-life, blocking the actions of strong

agonists (eg, heroin) for up to 48 h after oral use.

2-Naltrexone decreases the craving for ethanol and is approved for e

use in alcohol dependency programs.

3- Unlike the older drug two new antagonists

, t

do not cross the blood-brain barrier. These agents block adverse
effects

of strong opioids on peripheral μ receptors, including those

in the gastrointestinal tract responsible for constipation, with

minimal effects on analgesic actions

Done by

Ali Kareem