Opioid analgesics (VK)

Narcotic analgesics – opium plant – poppy plant - capsule

These neurons release excitatory neurotransmitters which relay signals from one neuron to another.

“The signals are sent to the thalamus, in which pain perception occurs. From the thalamus, the signal travels to the somatosensory cortex in the cerebrum, at which point the individual becomes fully aware of the pain (2).”

Pain Signaling

Types of Pain

Types of Pain – contd.

Opioids

Narcotic analgesics

Prototype: MORPHINE

Major action - CNS/spinal cord

Potent analgesia–Mu receptor agonist

Mu, Kappa, Sigma, Delta

Opioid receptor decreased calcium decreased glutamate decreased excitation

Opioid Analgesics – important terms Analgesics: Drugs -selectively relieves pain-

acting in the CNS or on peripheral pain mechanisms(without significantly altering the consciousness) – Opioids and NSAIDS

Opioids: drug binds -opioid receptors-antagonized by Naloxone .

– Natural, Synthetic and semi-synthetic Narcotics: Drugs-opium or opium like

compounds-potent analgesic effects-a/w significant alteration of mood and behavior-with the potential for dependence and tolerance-repeated administration.

Agonist Antagonist

Mu Strong: Morphine, Pethidine, Methadone, Levorphanol, fentanyl, alfentanil, sufentanil, remifentanil

Moderate: Oxycodone, codeine

Weak: Propoxyphene

PA: Buprenorphine- (long)

Naloxone

Naltrexone

Nalmefene

Nalbuphine

PentazocineNalorphine – weak antagonistButorphanol – weak antagonist

kappa Nalbuphine,PentazocineButorphanol, Nalorphine

Naloxone, Naltrexone

Nalmefene

Delta Naloxone, Naltrexone , Nalmefene

Nalorphine (weak antagonist)

Butorphanol – weak antagonist

Sigma Naloxone, Naltrexone,

Nalmefene

OPIOID/OPIATE RECEPTORSMu = µ Delta = δsupraspinal analgesia, euphoria, respiratorydepression, physical dependence

µ1 = mainly analgesia

µ2 = mainly respiratory depression

Kappa = κ = spinal analgesia, miosis, sedation

Sigma = σ = Dysphoria, halluci, respiratory depr and vasomotor stimulation

Where are the receptors ? Limbic system including amygdaloid nucleus,

hypothalamus Medial and lateral thalamus, area postrema

(CTZ) Nucleus of tractus solitarious (cough center) Substantia nigra, and spinal cord

Terminology Opioid agonist = activates some or all opioid

receptors and do not block any. Partial agonist = a drug that can activate

opioid receptor, but the response is submaximal

Mixed agonist-antagonist = a drug that activates some receptor subtypes and blocks some other subtypes

Pure antagonist = a drug that blocks all receptor subtypes

OPIOID RECEPTOR TRANSDUCER MECHANISMS

Mechanism of action

Opioid drug bind to opioid receptor widely distributed in CNS & other tissues

A part of family of G-protein complex receptor

Open K+ channels Prevent opening of Ca 2+ channels Inhibit the release of other neurotransmitters

Endogenous Opioid Peptides

3 distinct families of peptides

Enkephalins Endorphins Dynorphins Each family -derived - distinct precursor of

polypeptide

Acute effects

-Analgesia

-Dose dependent CNS depression

-Respiratory depression– medulla

-Histamine release – hypotension, peripheral vasodilation (decreased preload,afterload) bronchospasm

-Cough suppressant

-Decrease GI motility – constipation

Stimulant actions Euphoria, CTZ – N, V Increased ICT PINPOINT PUPILS - III N nucleus NOTE : Meperidine (Pethidine)

(ATROPINE- LIKE – MYDRIASIS) Biliary sphincter contraction Increased detrusor, sphincter tone

urgency but retention Uterine stimulation

Uses

Severe acute shooting visceral pain MI Terminal stages in malignancy Severe crush injuries Postoperative pain

Contraindications/A/E

Respiratory depression -Old, young,COPD, kyphoscoliosis Hypovolemia, hypotension Increase ICT HEAD INJURY Increased intrabiliary pressure UNDIAGNOSED ACUTE ABDOMEN Liver disease, renal disease Labor: respiratory depression in newborn

Acute morphine poisoning Respiratory depression, hypoxia Profound CNS depression, coma Hypotension, PINPOINT PUPILS

Use antagonist NALOXONE 0.4 mg IV q 2-3 min – pure

anta- competitive – all receptors VENTILATORY SUPPORT NARROW MARGIN OF SAFETY

Chronic effects Dependence – physical, psychic Tolerance – Effect goes on decreasing on

chronic use. Tissue tolerance – means - some tissues do

not get tolerant. CNS develops tolerance, but GIT (constipation)

and EYE (pinpoint pupils) do not develop tolerance !!

So, Opiate addict has constipation and pinpoint pupils

How to treat – Morphine dependence Substitute an agonist ! Which will be less potent than original drug – and - which will have long duration of action This will give similar pleasure and withdrawing this

drug will be easier due to long duration of action

(withdrawal symptoms will be less severe) So – 1. Methadone (long duration of action)

or 2. Buprenorphine (mild withdrawal)

Opiate withdrawal symptoms Hyperalgesia muscle cramps, stomach pain Mydriasis Diarrhea, Insomnia, Anxiety, Craving,

Sweating, Rhinorrhea, Tachycardia, increased blood pressure

Treat with – Methadone or buprenorphine (as replacement) Clonidine Beta blockers Benzodiazepines

What is heroin?

Heroin, not heroine !!

What is heroin?

Synthetic derivative of morphine (diacetyl morphine) Similar properties Treatment of overdose or withdrawal –

same as morphine

Heroin’s effects on the body

Important opioids

Analgesia (MI, terminal cancer pain, post-op) -Meperidine(pethidine)- atropine-like -fentanyl (also as patches) -methadone, buprenorphine

Others: -oxycodone, hydrocodone, propoxyphene Diarrhea – diphenoxylate, loperamide Cough-codeine, dextromethorphan

Pethidine (agonist) Opioid agonist, but is an atropine substitute So, atropine-like effects: Less spasmogenic, less

sphincter contraction No urinary retention, produces MYDRIASIS Less histamine release, safe in asthma PO, IV, IM 50-100 mg. Short duration – 2-3 hours Slow tolerance and dependence Uses: Preanesthetic medication Post-operative pain, other severe pains For analgesia during labor

Fentanyl (agonist) Congener of pethidine, Rapidly enters brain Short duration of action: 30-40 min

During anesthesia as analgesic - IV Post-operative pain - IV Along with droperidol (neuroleptanalgesia)-IV Cancer pains – as patch Chronic pains – as patch

IV: 1-2 mcg/kg Transdermal patch – 25-50 mcg per hour –

this acts for 2-3 days

Methadone (agonist) (long duration)

T1/2 – 24-36 hours, Slow persistent action Less abuse potential Withdrawal gradual, prolonged, less

severe 1 mg methadone = 4 mg morphine = 2 mg

heroin = 20 mg Pethidine Is also Analgesic 2.5 – 10 mg oral or im Used as substitute to treat morphine

addiction

Mixed agonist-antagonists Commonly used: Pentazocine Mu antagonist, K agonist: So, Good analgesic Oral (50-100 mg),IV IM (30-60 mg) Short duration of action Post-operative pain Pain due to burn, trauma, fracture, cancer Analgesia during anesthesia and other

procedures

Increases heart rate, BP, Remember: Do not use in MI

Remember: such a drug can precipitate withdrawal in a morphine addict due to Mu antagonistic effect

Diphenoxylate (Lomotil) therapeutic use is as antidiarrheal

drug (treats diarrhea) meperidine type drug has very little analgesic properties at

therapeutic dose no antitussive effect at high doses- analgesic problems causes respiratory depression and

euphoria at high doses

Codeine change in the methyl group on 3 position one tenth the potency of morphine the absorption is more regular than morphine and

more predictable metabolized like morphine through glucuronic

acid tolerance and physical dependence is protracted

from morphine since potency of codeine is low withdrawal from codeine is mild in relation to

morphine antitussive drug for cough

Structural Activity Relationship

O

HOH

NH

CH3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

Morphine (Astramorph)

HO- Group is needed for activity

HO- Group not important to activity

O

HOH

NH

CH3

CH3O

Codeine (5X LESS potent than morphine)

Inefficiently converted to HO group in the liver

PURE ANTAGONIST

Pure antagonists Naloxone – for acute morphine

poisoning – 0.4 mg IV q 2-3 min

Naltrexone – tablet 50 mg qd - is of more benefit to decrease the sensation of craving during treatment of addiction – opiates, alcohol, and other drugs of abuse

Nalmefene

Naloxone no analgesic activity at all competitive antagonist at mu, kappa, and

sigma receptor displaces morphine and other OPIOID from

receptor site reverses all actions of the OPIOID and does

it rather quickly it will precipitate withdrawal increases blood pressure metabolized same as morphine through

glucuronic acid conjugation and excreted through kidney

Naltrexone same effect of naloxone except -used orally so

can't be used for person with acute toxicity long duration of activity single dose block action of heroin-24 hours used for emergency treatment once stabilized, give patient naltrexone After giving naltrexone patient- no euphoric

effect from heroin so person gets off heroin (negative reinforcement)

approved for use by the FDA also used for treatment of alcoholism 

Pharmacokinetics of opoids

Absorption from GI tract, nasal mucosa, lung. Also through subcutaneous, intramuscular, and

intravenous route

Distribution Bound/free morphine accumulates- kidney,

lung, liver, and spleen CNS is primary site of action

(analgesia/sedation)

Metabolism/Excretion metabolic transformation -liver conjugates with glucuronic acid excreted by kidney - glomerular filteration half life -2.5 to 3 hours morphine 3 glucuronide - main excretion

product 90% is excreted in first day. duration of 10 mg dose- 3 to 5 hours

Drug interactions with Opioids in general, the

coadministration of CNS depressants with OPIOID often produces at least an additive depression (potentiation)

OPIOID and phenothiazines produces an additive CNS depression as

well as enhancement of the actions of OPIOID (respiratory depression)

this combination - orthostatic hypotension OPIOID and tricyclic

antidepressants produce increased hypotension meperidine and MAO inhibitors - severe

and immediate reactions that include excitation, rigidity, hypertension, and severe respiratory depression

OPIOID and barbiturates increased clearance

morphine and amphetamine enhanced analgesic effect