Kuswinarti

Department Pharmacology and Therapy

Medical School Padjadjaran University
 INTRODUCTION
OPIOIDS :
Natural / synthetic compounds
morphine-like effects
Act by binding to specific opioid receptors CNS
effects mimic action ENDOGENOUS PEPTIDE
NEUROTRANSMITTERS (Endorphines ,
Enkephalins)
Primary use : relieve intense pain & anxiety
surgery, injury/disease (such as : cancer)
Drug abuse
Opioids antagonist very important
clinically in case of OVERDOSE
 OPIOID RECEPTORS
Four families of receptors :
(Mu) :
Supraspinal analgesia, respiratory depression,
euphoria/sedation, physical dependence,
decreased GI motility, pupil constriction
(Kappa) :
Spinal analgesia, sedation/dysphoria, pupil
constriction
(Sigma) :
Dysphoria, hallucinations,psychotomimetic effects,
pupil dilation
(Delta )
 CLASSIFICATION
1. Strong agonists
Fentanyl - Heroin
Meperidin - Methadone
Morphine - Sufentanil
2. Moderate agonists
Codeine - Propoxyphene
3. Mixed agonist-antagonist
Buprenorphine - Pentazocine
4. Antagonist
Naloxone - Naltrexone
 MORPHINE

MOA :
Opioids + R-opioids (CNS,GIT)
Act at -R in spinal cord release substance P
which modulates pain perception
Inhibit release excitatory transmitter from nerve
terminals carrying nociceptive (painful) stimuli
 ACTIONS
Analgesia :
Opioid relieve pain pain threshold +
altering brains perception of pain
Euphoria
Produces a powerful sense of
contentment and well-being
Respiration
Sensitivity of respiratory center neurons
to CO2 Respiratory depression
Respiration ceases death (acute
opioid overdose)
 Depression of cough reflex
Morphine & codeine antitussive
Miosis
Characteristic pinpoint pupil
Emesis
Stimulate the chemoreceptor trigger zone
vomiting
GIT
Relieve diarrhea & dysentery
Smooth muscle motility , tone
Biliary tract pressure
Anal sphincter tone
CONSTIPATION
 CVS :
Has no major effects on the blood
pressure or heart rate , except at large
dose
( hypotension & bradycardia)
Respiratory depression & CO2 retention,
cerebral vessels dilate & CSF pressure
CI : patient severe brain injury

Histamine release :
Release histamine urticaria, sweating
Bronchoconstriction dont give to
asthma patient
 Hormonal actions :
Inhibits release GnRH , CRH LH, FSH,
ACTH Testosterone, Cortisol levels
Antidiuretic hormone (ADH) urinary
retention

Therapeutic Uses :
Analgesia
Treatment diarrhea
Relief of cough :
Suppresses the cough reflex
Codeine & dextromethorphan are widely used

Codeine > antitussive action than morphine

 PHARMACOKINETICS
Adm :
Abs from GIT is slow & erratic ( orally )
Codein : Abs PO >
Significant FPM in the liver
Non medical purposes : inhalation of the smoke from burning
crude opium rapid OOA

Distribution :
rapidly enters all body tissues, including the fetuses
( analgesia during labor)
Infants born of addicted mothers physical dependence ,
withdrawal symptoms
Small % enter BBB ( morphine <lipophilic than fentanyl,
heroin)

Fate
Morphine Morphine-6-glucoronide (very potent analgesic) +
conjugate at the 3-position (inactive) E : Urine (primarily) +
bile (small)
DOA : 4-6 hours
 Adverse effects :
Respiratory depression
Nausea & Vomiting
Sedation
Allergy-enhanced hypotensive effects
Urinary retention
Constipation

Tolerance and physical dependence

Drug interactions :
Phenothiazine, MAO inhibitors, tricyclic
antidepressant Depression actions of
morphine
Amphetamine, hydroxyzine analgesia
 MEPERIDINE
Synthetic opioid
MOA :
Bind to opioids receptors, particularly -receptors
ACTIONS :
Depression respiration
PO no significant CVS action
IV cardiac rate
GIT : chronic use constipation
pinpoint pupil ; atropine-like activity (pupils
dilation)
THERAPEUTIC USES :
Provides analgesia for any type of severe pain
 PHARMACOKINETICS :
Well absorbed from GIT ; most often adm : IM
DOA 2-4 hours ( > shorter than morphine)
Preferred for analgesia during labor

ADVERSE EFFECTS :
Large doses : tremors, muscle twitches, convulsion
(rarely)
Postoperatively: severe hypotension
+ major neuroleptic depression
+ MAO inhibitors convulsion, hyperthermia
Cause dependence can substitute for morphine
or heroin in use by addicts
Cross-tolerance
 METHADONE
Synthetic opioids, PO effective
Potency ~ morphine ; < euphoria , > DOA
MOA :
Greatest action on -receptors
ACTIONS :
Analgesic activity ~ morphine
PO : Strong analgesic action
Miotic & respiratory depressant
Constipation
 Therapeutic uses :
Controlled withdrawal of addicts from
heroin & morphine
PO adm substituted for injected opioid
Milder withdrawal syndrome
Pharmacokinetics :
PO readily abs , DOA > morphine
Adverse effects :
Produce dependence
Withdrawal syndrome : mild , > protracted
( days to weeks)
 FENTANYL
80 X analgesic potency of morphine
used : anesthesia
Rapid onset & short DOA (15-30 minutes)
Sufentanil > potent

HEROIN
Acetylation of morphine potency 3 x >
Lipid solubility BBB Euphoria
Has no accepted medical use
 MODERATE AGONISTS

PROPOXYPHENE
Dextro isomer analgesic to relieve mild to
moderate pain
Levo isomer antitussive action
Combination with acetosal /acetaminophen
analgesia
PO : well abs., Tmax = 1 h
SE : nausea, anorexia, constipation
Toxic doses : respiratory depression, convulsion,
hallucinations, confusion >< NALOXONE
 CODEINE

Less potent analgesic than morphine

Higher oral efficacy
Antitussive activity
Lower abuse potential , rarely
produces dependence
Less euphoria
MIXED AGONIST-ANTAGONISTS
Pentazocine, Buprenorphine

Stimulate one receptor but block

another
Effects depend on previous exposure
to opioids
Patient has not recently received opioids
- show agonist activity
Patient with opioid dependence
blocking effects withdrawal symptoms
 ANTAGONISTS

Bind with high affinity to opioid

receptors but fall to activate the
receptor-mediated response
In patients addicted to opioids
rapidly reverse the effect of agonist
 NALOXONE
Reverse the coma & respiratory
depression of opioids overdose
Competitive antagonist at ,,-receptors
affinity for -receptor 10 x > -receptor
Produces no pharmacologic effects in
normal individuals, >< withdrawal
symptoms in morphine or heroin abusers
NALTREXONE
Action similar Naloxone, but DOA >
Used in opiate-dependence maintenance
programs & treating chronic alcoholism