Opioid analgesics and antagonistdo.rsmu.ru/fileadmin/user_upload/pf/Analgetics_MF.pdfAnalgesic is a...

Opioid analgesics and

antagonist

Pain Management

What is a pain?

– A protective mechanism to warn of damage or the

presence of disease

– Part of the normal healing process

Pain is a warning signal and primarily protective in nature, but causes discomfort. It is the most important symptom that brings the patient to the physician.

Pain can be either acute or chronic and is a consequence of complex neurochemical processes in the peripheral and central nervous systems (CNS).

Analgesic is a drug that selectively relieves pain by

acting in the CNS or on peripheral pain mechanism,

without significantly altering consciousness.

Analgesics relive pain as a symptom, without affecting

its cause. They are used when the noxious stimulus

(evoking pain) cannot be removed or as adjuvants to

more etiological approach to pain.

Analgesics

Opioid (narcotic): Morphine like analgetics

Nonopioid (non-narcotic): 1. Aspirin like -

antipyretic or antiinflammatory analgesics.

2. Antidepressants

3. Antiepileptic drugs

4. General anesthetics and others

Natural

•Morphine

•Codeine

Semi-Synthetic

•Diacetylmorphine

(heroin)

•Naloxone

(antagonist)

Fully Synthetic

•Pethidine

(meperidine)

•Tramadol

•Nalbuphine

•Methadone

•Pentazocine

•Fentanyl

•Alfentanil

•Sufentanil

•Remifentanil

Classification by origin

Classification of OPIOIDS AND

OPIOID ANTAGONISTSStrong (Full) agonists

Morphine

Fentanyl

Diacetylmorphine (Heroin)

Pethidine (Meperidine)

Alfentanil, Sufentanil, Remifentanil

Methadone

Moderate agonist:

Codeine

Partial/weak µ agonist + κ antagonist

Buprenorphine

Classification of OPIOIDS AND

OPIOID ANTAGONISTSAgonist-antagonists ( analgesics)

Nalorphine

Pentazocine

Butorphanol

With mixed mechanism of action

Tramadol

Pure antagonists

Naloxone

Naltrexone

Nalmefene

Receptor Distribution

and Neural Mechanisms

of Analgesia:

Transmission

Mechanism of Action

Opioid analgesics bind to several different opioid receptors in the CNS and spinal cord

Opioid receptors

group of G-protein coupled receptors with

opioids as ligands.

The endogenous opioids are dynorphins,

enkephalins, endorphins, endomorphins and

nociceptin.

Subtypes of opiod receptors:

mu, delta, kappa, epsilon, sigma

Mechanism of action

Closing voltage-gated Ca2+ channels on

presynaptic nerve terminals. As result to Inhibit

release of

Glutamate, acetylcholine, norepinephrine,

serotonin, and substance P

Hyperpolarizing and thus inhibiting postsynaptic

neurons by opening K+ channels

A. Effects due to μ-receptor stimulation:

• Supraspinal, spinal & peripheral analgesia

• Euphoria

• Respiratory depression

• Miosis

• Decreased GIT motility,

• Sedation

• Physical dependence.

.

B. Effects due to қ-receptor stimulation:

• Spinal and peripheral analgesia,

• Dysphoria

• Sedation

• Respiratory depression (less)

• Miosis (less)

• Decrease GIT motility

• Physical dependence

C. Effects due to δ-receptor stimulation:

• Spinal analgesia

• Respiratory depression

• Decrease GIT motility .

• They are not true opioid receptors only

some opioids react with them .

D. Effects due to other receptors stimulation:

Stimulation of σ receptors produces autonomic stimulation, dysphoria, hallucinations, nightmares, and anxiety.

Stimulation of ε receptors produces analgesia.

4

Opiod Receptor Activation

Response Mu-1 Mu-2 Kappa Delta Sigma

Analgesia

Respiratory depression

Euphoria

Dysphoria

Decrease GI motility

Physical Dependence

Mania, hallucination

Effects of opioid analgesics

(morphine)

Central effects

Inhibitory Effects

1. Analgesia. The analgesic action has spinal and

supraspinal components. It acts in the substantia

gelatinosa of dorsal horn to inhibit release of excitatory

transmitters from primary afferents carrying pain impulses.

Action at supraspinal sites in medulla, midbrain, limbic and

cortical areas may alter processing and interpretation of

pain impulses as well as send inhibitory impulses through

descending pathways to the spinal cord.

Inhibitory Effects

2. Sedation. This effect is different from that produced by

hypnotics. Drowsiness and indifference to surrounding as

well as own body occurs without motor incoordination,

ataxia or apparent excitement (contrast alcohol). Higher

doses progressively cause sleep and coma. It has no

anticonvulsant action.

3. Respiratory Depression

- Significant respiratory depression by reduction of the

sensitivity of respiratory center neurons to carbon dioxide

Influenced significantly by the degree of sensory input

Respiratory depression is the most common cause of death

in acute opioid overdose.

Inhibitory Effects

4. Cough Suppression

Depression of cough reflex by depression cough center(Codeine more effective)

5. Temperature regulation. Morphine cause depression

of temperature regulating centre, hypothermia occurs,

but no antipyretic action.

-opioid receptor agonists hyperthermia

-opioid receptor agonists hypothermia

6. Vasomotor center is depressed at higher doses and

contributes to the fall in BP.

Inhibitory Effects

7. Hormones. Inhibiting of secretion of ACTH, GTH and

LH

8. Vomiting center is depressed.

Stimulating Effects

1.Euphoria Mood and subjective effects. These are

prominent. It has a calming effect, very pleasurable –

akin to orgasm. Pleasant floating sensation. Lessened

anxiety and distress

Dysphoria may occure

2. Emesis. Directly stimulation of the chemorecetor

trigger zone in the area postrema that causes vomiting.

Stimulating Effects

3.Miosis as result of III nerve stimulation (from stimulation

of μ and κ receptors). There is little tolerance to the

effect, and all addicts demonstrate pin-point pupils. This

is important diagnostically, because most other causes

of coma and respiratory depression produce dilation of

the pupil.

4. Vagal center is stimulated too – can cause bradycardia

and hypotension.

5.Hormonal action. Stimulation of releasing ADH, GH,

PL.

6. Truncal Rigidity

Intensification of tone in the large trunk muscles

Peripheral effects

Inhibitory Effects

1. GIT. Decreasing motility of smooth muscle. As result

produces constipation, with little tolerance developing.

2. Venodilation. Because of respiratory depression and

carbon dioxide retention, cerebral vessels dilate and

increase the cerebrospinal fluid (CSF) pressure.

Therefore, Morphine is usually contraindicated in

individuals with severe brain injury.

Stimulating Effects

1. CVS. Morphine has no major effects on the blood

pressure or heart rate except at large doses, when

hypotension and bradycardia may occur.

Except agonist-antagonists, that have sympathetic activity

and lead to hypertension and tachycardia.

2. GIT. Increasing tone of smooth muscle. It increases

pressure in the biliary tract, because causes spasm of

sphincter Oddi ( may cause biliary colic). It also increases

the tone of the anal sphincter.

3.Urinary bladder. Tone of both detrusor and sphincter is

increased, urinary urgency and difficulty in micturition are

occur.

Stimulating Effects

4. Bronchi. It causes histamine release which can cause

bronchoconstriction.

5. Histamine release. Releasing histamine from mast

cells, causing urticaria, sweating and vasodilation.

Because it can cause bronchoconstriction, asthmatics

should not receive the drug.

Morphine

It is the principal opium alkaloid, therefore described as

prototype. It shows a high affinity for μ receptors, varying

for δ and κ receptors, and low affinity for σ receptors

(The major effects of the opioids are mediated by these

receptors).

1. Analgesia:

- Used for various pain, especially acute, obstinate constant

pain (e.g. burn, cancer pain);

2. Cardiac asthma:

Acute left ventricular heart failure induces pulmonary edema

- Reduces anxiety, cardiac preload and afterload.

- Particularly useful for painful myocardial ischemia with

pulmonary edema.

3. Treatment of diarrhea (Loperamide)

4. Relief of cough

5. Premeditate drugs before anesthesia : sedative,

anxiolytic, and analgesic properties. For high-risk surgery

administered systemically; for local (epidural) anesthesia.

Indications

1. respiratory depression, apnea2. nausea and vomiting3. Dysphoria4. dizziness, orthostatic hypotension, edema5. mental clouding, drowsiness6. constipation, ileus7. biliary spasm (colic)8. dry mouth9. urinary retention, 10. hypersensitivity reactions (contact dermatitis, urticaria)11. Elevation of intracranial pressure (head injury)12. Tolerance and Physical Dependence

Adverse Reactions

Withdrawl Reactions

Acute Action• Analgesia

• Respiratory Depression

• Euphoria

• Relaxation and sleep

• Tranquilization

• Decreased blood pressure

• Constipation

• Pupillary constriction

• Hypothermia

• Drying of secretions

• Reduced sex drive

• Flushed and warm skin

Withdrawl• Pain and irritability

• Hyperventilation

• Dysphoria and depression

• Restlessness and insomnia

• Fearfulness and hostility

• Increased blood pressure

• Diarrhea

• Pupillary dilation

• Hyperthermia

• Lacrimation, runny nose

• Spontaneous ejaculation

• Chilliness and “gooseflesh”

Meperidine

It is a synthetic opioid with a structure unrelated to Morphine.

It is used for acute pain.

It binds to opioid receptors, particularly κ receptors.

It causes a depression of respiratory similar to that of Morphine, but there is no significant cardiovascular action when the drug is given orally.

Meperidine

It is a synthetic opioid with a structure unrelated to Morphine.

It is used for acute pain.

It binds to opioid receptors, particularly κ receptors.

It causes a depression of respiratory similar to that of Morphine, but there is no significant cardiovascular action when the drug is given orally.

It dilates cerebral vessels and increases cerebrospinal fluid pressure similar to that of Morphine and in contrasts it does not cause pinpoint pupils and has a little effect on gastrointestinal tract and urinary bladder.

Meperidine provides analgesia for any type of severe pain, but is not clinically useful in the treatment of diarrhea or cough. It produces less of an increase in urinary retention than does Morphine.

Meperidine

Fentanyl

It is chemically related to Meperidine, has 80 -

100 times more potent than Morphine, both in

analgesia and respiratory depression.

The duration of action is short: starts wearing

off after 15-30 minutes.

It is almost exclusively used in anesthesia,

mostly in combination with Droperidol.

Codeine

It is a much less potent analgesic than

Morphine, but it has a higher oral efficacy. It

shows good antitussive activity at doses that do

not cause analgesia.

It rarely produces dependence, because

causes less euphoria than Morphine.

It is often used in combination with Aspirin and

as antitussive drug.

Pentazocine

It acts as an agonist on κ receptors and is a weak antagonist at μ and δ receptors. It also binds to σ receptors, which may account for its dysphoric properties.

In higher doses, the drug causes respiratory depression and decreases the activity of the gastrointestinal tract. High doses increase blood pressure and can cause hallucinations, nightmares, tachycardia and dizziness.

Pentazocine

Despite its antagonist action, Pentazocine does not

antagonize the respiratory depression of Morphine,

but it can precipitate a withdrawal syndrome in a

Morphine abuser.

It can used as analgesic.

AntagonistsNaloxone and Naltrexone

They are used to reverse the coma and

respiratory depression of opioid overdose.

Naltrexone has a longer duration of action than

Naloxone (48 hours and 6 hours).

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