2. Opioid Analgesics & Antagonists

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OPIOID ANALGESICS& ANTAGONISTS

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Opioids: natural or synthetic compounds morphine-like effects

Opiates:a term reserved for those drugs,

such as morphine or codeine, obtained from

the juice of opium poppy Papaver

somniferum

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Opium Poppy4


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Commercial poppycultivation in France

Capsule ofPapaversomniferumshowing latex

(opium) exuding from incision

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http://en.wikipedia.org/wiki/File:Papver_field_france.jpghttp://en.wikipedia.org/wiki/File:Slaapbol_R0017601.JPG


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Endogenous opioids: endorphins,

enkephalins, dynorphins & even morphine

itself

Morphine mimics endogenous endorphinsresponsible for analgesia (pain reduction or

relief) sleepiness & feelings of pleasure They are released in response to pain,

strenuous exercise, orgasm or excitement.

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Opioid receptors:

mu (), kappa () &

delta (), through G-

proteins (Gi),

1) Facilitate opening of K+

channels hyperpolarization

2) --- Adenylate cyclase

cAMP

3) --- Ca2+ channels opening

transmitter release

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-Receptors analgesia, sedation, miosis,euphoria, respiratory depression, GI motility

depression & dependence

-Receptors analgesia, sedation, miosis &dysphoria

-Receptors,more important in theperiphery, may contribute to analgesia

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ANALGESIASedation

Miosis

EUPHORIA

Respiratory depression

GI motility depression

Dependence

-Receptors

-Receptors

-ReceptorsDYSPHORIA

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Opioid Agonists & Antagonists

I. Pure AgonistsII. Mixed Agonist-

Antagonists III.AntagonistsA.STRONG AGONISTS B.MODERATE AGONISTS

1.Morphine

2.Diamorphine(Heroin)

3.Meperidine4.Methadone5.Fentanyl6.Sufentanil7.Etorphine

1.Propoxyphene

2.Codeine1.Pentazocine

2.Cyclazocine3.Nalorphine4.Nalbuphine5.Buprenorphine

1.Naloxone

2.Naltrexone

3.Nalmefene

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I.STRONG AGONISTS

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1. Morphine

Thegold standardof analgesics used to

relieve severe or agonizing pain & suffering

Acts directly on the CNS

A high potential for addiction; tolerance and

both physical and psychological dependencedevelop rapidly

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Mechanism of action

Interaction with opioid receptors in the CNS &

GIT 1) hyperpolarization of nerve cells -- nerve firing2) presynaptic inhibition of transmitter release

At -receptors release of substance Pwhich modulates pain perception

-- release of many excitatory transmitters

from nerve terminals carrying painful stimuli

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Pharmacological Effects

1. CNS:

a) Analgesia & sedation

b) Euphoria

c) Respiratory depression

d) Depression of cough reflex (antitussive)

e) Nausea & vomiting

f) Miosis

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Pharmacological Actions (Contn.)2. Smooth muscles (GIT, urinary T., bronchi

& uterus)

3. Cardiovascular & cerebral b.v.

4. Histamine release

5. Hormonal actions

6. Straub tail reaction

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Tolerance & Dependence

Repeated administration tolerance to theanalgesic, sedative, euphoric & respiratorydepressant effects.

Tolerance DOES NOT develop to thepupillary

constriction&constipation.

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Physical & psychological dependencereadily

occur with morphine.

Withdrawal abstinence symptoms; a seriesof autonomic, motor and psychological

responses that incapacitate the individual serious, almost unbearable symptoms

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Pharmacokinetics

GI absorption is slow & erratic.

Significant hepatic 1st pass metabolism to

glucuronides

Other routes of administration should be

followed; i.m., s.c., i.v., inhalation!!!

The duration of action of morphine is 4-6

hours in naive individuals.

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Morphine rapidly enters all body tissues,

including the fetus of pregnant women.

Infants born of addicted mothers show

physical dependence on opiates and exhibitwithdrawal symptoms if opioids are not

administered.

Morphine is the least lipophilic opioid onlya small % crosses the BBB

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Side effects

1. Severe respiratory depression??

2. Other effects: vomiting, dysphoria &

allergy-enhanced hypotensive effects

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Precautions & Contraindications

1. Infants & elderly (more sensitive to resp. dep.)

2. Resp. insufficiency (e.g. emphysema, fibrosis)

3. Bronchial asthma

4. Head injury !!!

5. Hypotensive states & hypovolemia

6. Undiagnosed abdominal pain !!!

7. Prostatic hypertrophy retention

8. Adrenal insufficiency or myxedema extended &

enhanced effects(patients are more sensitive to morphine)

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Uses

1. Analgesia ?

2. Diarrhea & dysentry ?

3. Antitussive ?

4. Acute pulmonary edema (i.v.) secondary

to left ventricular failure (cardiacasthma) ?

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2. Diamorphine (heroin; diacetylmorphine)

morphine in the body More potent than morphine (2-4) A greater lipid solubility

1) Crosses BBB more readily than morphine

2) Smaller doses can be given orally

A shorter duration of action than morphine

Similar to morphine, diamorphine resp.depression & physical dependence

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3. Meperidine (pethidine)

1st synthetic opioid (1939) with additional

antimuscarinic properties !!!!

Similar to morphine in pharmacological effects

except that it tends to cause RESTLESSNESS !!

rather than SEDATION.

A faster onset & a shorter duration of action

A similar euphoric effect & equally liable to

cause dependence

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Used in moderate to severe pain:

Pethidine is superior to morphine in Rxpain

associated with biliary spasm or renal colic due

to its antispasmodic effects. G.R.

It is preferred for analgesia during labor (due

to its shorter duration of action (120-150 min)

less resp. depression than morphine)G.R. Concurrent administration of pethidine with

MAOIs severe reactions; excitement,hyperthermia & convulsions death(serotonin syndrome)

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t 8-12 h

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The severe side effects unique to pethidine -

serotonin syndrome, seizures, delirium, dysphoria

& tremor- are due to norpethidine.

Norpethidine is toxic and has convulsant and

hallucinogenic effects.

These toxic effects CANT be countered with

naloxone because they are due to its

anticholinergic activity & monoamine (NE,

dopamine & 5-HT) reuptake inhibition.

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1/8th the potency of morphine

Well absorbed orally

Biotransformed to a toxic metabolite (norpethidine)

that can cause seizures

A faster onset & a shorter duration !!!

Fewer smooth muscle spasms than morphine !!!

Less histamine release safer in asthmatic

No miosis

Tachycardia

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4. Methadone

1) A synthetic, orally effective opioid that is equalanalgesia in potency to morphine

2) Less euphoria & sedative actions blockade of

euphoric effects of heroin, morphine & similar drugs

3) A long duration of action due to long plasma t1/2 (

24 h) & duration of action with repeated use

1, 2 & 3 use in controlled withdrawal of addicts

from heroin & morphine (anti-addictive)

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5. Fentanyl & sufentanil & alfentanyl

Highly potentphenylpiperidine derivatives, with

actions similar to morphine, but short-lasting,

particularly sufentanil

Fentanylis 80-100 more potentthan morphine

Sufentanilis a highly potent analgesic (5-10 more

potent than fentanyl) used in heart surgery.

Alfentanilis an ultra-short acting(5-10 minutes)

opioid.

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Fentanyl is extensively used for anesthesia&analgesia, most often in the operating room

and intensive care unit.

Fentanyl is sometimes given intrathecallyaspart of spinal anesthesia or epidurallyfor

epidural anesthesia & analgesia.

Fentanyl is available as a patch & as an oral

slow-release device

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6. Etorphine:

A semi-synthetic morphine analogue with an

analgesic potency 1000-3000 that ofmorphine(but otherwise very similar in its

actions)

Used to immobilize wild large animals, like

elephants, for trapping & research purposes.

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Tramadol

Opioid receptor agonist

A low affinity for receptors and a very low affinity

for & !!!!

NE & 5-HT reuptake blocker (antidepressant) & 2adrenoceptor agonist

These 2 actions are synergistic for analgesia

Analgesic action is partially reversed by naloxone

Used in mild-to-moderate short-lasting pain &

chronic pain

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II.MODERATEAGONISTS

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1. Codeine

More oral absorption than morphine (due to

its higher lipid solubility)

A marked antitussive activity used incough mixtures

20% of the analgesic potency of morphine used as oral analgesic for mild types of

pain(headache, backache, etc.)

Little or no euphoria & rarely addictive

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2. Dextropropoxyphene

Well absorbed orally(peak plasma levels

occurring in 1 hour)

Similar to CODEINE but has a longer durationof action &free from dependence liability

Often used in combination with aspirin or

acetaminophen for a greaterANALGESIA than

that obtained with either drug alone

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III.MIXED AGONIST-

ANTAGONISTS(Pentazocine, Nalorphine&cyclazocine,

Butorphanol & Nalbuphine)

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1. Pentazocine ( partial agonist and & agonist)

At low doses, its potency & effects are very similar

to morphine.

Dose a corresponding in produced effects &at high doses, pentazocine slight resp. dep. ()

marked dysphoria, with nightmares &

hallucinations (), rather than euphoria

Used in moderate to severe pain

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Its antagonist activity is apparent when given

concurrently with morphine as pentazocine

the analgesic & other actions of morphine

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2. Nalorphine

In low doses, it competitively antagonizes

(blocks) most actions of morphine.

In high doses, it is analgesic, and mimic the

effects of morphine.

These effects reflect an antagonist action on

-receptors, coupled with a partial agonistaction on- and-receptors, the lattercausing dysphoria.

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IV.ANTAGONISTS(Naloxone, Naltrexone & Nalmefene)

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Signs of Overdose

o stuporous or in coma

o low body temp.

o pinpoint pupils

o extremely low resp. rate (resp. dep.)

o flaccid skeletal muscles, relaxed jaw

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1. Naloxone

Naloxone is used to reverse the resp.

depression & coma of opioid overdose.

It rapidly displaces all receptor-bound

opioids reversal of heroin overdose effect Within 30 seconds of its i.v. injection, the

resp. depression & coma; characteristics ofhigh doses of heroin, are reversed thepatient is revived and alert

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A short t1/2 of60-100 min.

Not effective orally

In normal individuals, naloxone nopharmacologic effects, but it precipitates

withdrawal symptoms in morphine or heroin

abusers

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2. Naltrexone

Actions similar naloxone

A long t1/2a longer duration of action thannaloxone; a single oral dose blocks the effectof injected heroin for up to 48 hours

Available in oral form only

It is used in opiate-dependence maintenance

programsand chronic alcoholism.

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3. Nalmefene

Intermediate duration (4-6 hr)

orally active

no hepatotoxicity

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2. Opioid Analgesics & Antagonists

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