Opioid Analgesics

BY

PROF. AZZA EL-MEDANY

CLASSIFICATION

Natural ( Morphine) Semisynthetic ( Codine ) Synthetic ( Mepiridine, Methadone,

Fentanyl, Tramadol )

Another Classification

Strong agonist Moderate agonists Mixed agonists /antagonists Pure antagonist

Mechanism of actions

Binding to opioid receptors (mu,delta, kappa ,sigma ) at presynaptic nerve fibres resulting in decreasing calcium influx leading to decrease in releasing excitatory neurotransmitters

Post synaptic activation of receptors increase potassium efflux (hyperpolarization )

Morphine ( Natural & Strong agonist)

PHARMACOKINETICS : ROUTES OF ADMINISTRATION METABOLISM DISTRIBUTION EXCRETION

Routes of administration

Oral absorption is erratic IMI , SC injection are preferred Chronic pain , slow release preparation Non medical route , inhalation of powder

or smoke

Metabolism & excretion

In liver to active metabolite ( morphine -6 glucuronide & morphine -3 glucuronide

Half-life 4-6 hours. Crosses BBB & placental barrier Excreted in urine

Pharmacological actions

Analgesia

Without loss of consciousness

Severe type of pain

Sedation

Euphoria

Respiration

Respiratory depressant which is dose dependent

Large dose causes respiratory failure & death

Reduce the sensitivity of respiratory center to CO2

Eye

Miosis ( pin point pupil)

Through mu & kappa receptors at

Edinger westphal neuclus of 3rd nerve

Cough center

Antitussive

Potent depressant for cough center

Histamine release

From mast cells ( urticaria, sweating , vasodilataion , bronchospasm )

Endocrinal effect

Decrease : LH, FSH, ACTH , testosterone

Increase : Prolactin, growth hormone, ADH leading to urine retention

Nausea & Vomiting

Stimulation of CRTZ

GIT

Constipation Constrict biliary smooth muscle may

result in biliary colics Sphincter of Oddi may constrict

resulting in reflux of biliary & pancreatic secretions & elevated plasma lipase & amylase

Urinary System

Decrease in renal function Urine retention Spasm of smooth muscles of ureter

causing renal colics

Uterus

Prolong labor

CVS

Large dose causing hypotension & bradycardia

With respiratory depression & retention of CO2 causing cerebral vasodilataion & ↑ in CSF pressure

CLINICAL USES

CANCER PAIN SEVERE BURN SEVERE VISCERAL PAIN ( except, renal &

biliary colics , acute pancreatitis ) DIARRHOEA COUGH ACUTE PULMONARY OEDEMA Myocardial ischemia PREANAESTHETIC MADICATION

ADVERSE EFFECTS

RESPIRATORY DEPRESSION NAUESEA & VOMITING CONSTIPATION URINE RETENTION HYPOTENSION ALLERGY TOLERANCE ( not to mitotic, convulsant, or

constipating effects ) ADDICTION ( abstinence syndrome)

Withdrawal manifestations

Severe body ache Insomnia Diarrhea Goose flesh Lacrimation

CONTRAINDICATIONS

HEAD INJURY PREGNANCY BRONCHIAL ASTHMA or impaired

pulmonary function Liver & Kidney diseases (including

renal& biliary colics ) Endocrine diseases ( myxedema &

adrenal insufficiency)

Continue

Old people are more sensitive ( decrease in metabolism , lean body mass & renal function )

Not given to infants With MAOI

Meperidine ( Pethidine)

Synthetic Strong agonist More effective on kappa receptors

PHARMACOKINETICS

Well absorbed orally

(Has a high oral bioavailability ) Given also by IMI Half-life ( short ) 2-4 hours Give an active metabolite which has

CNS stimulant effect Excreted in urine

Pharmacological Actions

Less analgesic , less constipating ( weak effect ) , less depressant on foetal respiration than morphine

Atropine –like action Smooth muscle relaxant effect No cough suppressant effect

CLINICAL USES

Cancer pain Severe burn Severe visceral pain( renal & biliary

colics ) Obstetric analgesia Preanaesthetic medication

ADVERSE EFFECTS

Tremors & Convulsions Hyperthermia Hypotension Tolerance & Addiction Burred vision Dry mouth Urine retention

METHADONE

SYNTHETIC OPIOID POTENT ANALGESIC AS MORPHINE GIVEN BY ORAL , I.V., S.C., AND

RECTAL HAS A HIGHER ORAL

BIOAVAILABILITY THAN MORPHINE

CONTINUE

LONG PLASMA HALF- LIFE ( 24 hrs ) LESS EUPHORIC THAN MORPHINE PRODUCES MILD WITHDRAWAL

SYMPTOMS TOLERANCE & PHYSICAL

DEPENDENCE DEVELOP MORE SLOWLY THAN MORPHINE

CLINICAL USES

Control withdrawal symptoms of dependant abusers from heroin & morphine

Neuropathic & cancer pain

CODEINE

Synthesized commercially from morphine Less analgesic & euphoric than

morphine Given orally Potent antitussive Always given in combination with aspirin

or acetaminophen Addicting drug

DEXTROMETHORPHAN

FREE OF ANALGESIC & ADDICTIVE EFFECTS

LESS CONSTIPATING THAN CODEINE POTENT AS ANTITUSSIVE

Fentanyl

Synthetic drug More potent as analgesic than

morphine Rapid onset & very short duration of

action (15-30 min ) Used as I.V. anaesthesia IN cancer pain as transdermal patches Has a respiratory depressant effect

Sufentanyl, Alfentanyl & Remifentanil

Sufentanyl more potent than fentanyl Other two are less potent with shorter

duration of action

Heroin

Strong agonist Crosses BBB Converted to morphine No medical use Strong addicting drug

TRAMADOL ( Synthetis )

Centrally acting analgesic through inhibition uptake of norepinephrine & serotonin

Binds to mµ receptor. Less potent as analgesic than morphine Undergoes extensive metabolism

CONTINUE

Given orally ( high oral bioavailability) & by different other routes

Used in :

mild & moderate acute & chronic visceral pain

during labor

ADVERSE EFFECTS & CONTRAINDICATIONS

Seizures , Nausea , Dry mouth, Dizziness , Sedation

Less adverse effects on respiratory & C.V.S.

Contraindicated in patients with history of epilepsy

Loperamide

Can not cross BBB Lacking analgesic effect Used for treatment of chronic diarrhea

OPIOIDS WITH MIXED RECEPTORS ACTIONS

BUPRENORPHINE Partial Mu receptor agonist Long duration of action Poor oral bioavailability Given parntrally ,Sublingually , Or as

nasal spray Excreted in the bile & urine

CONTINUE

Acts as morphine in normal patient & precipitate withdrawal symptoms in morphine users.

Causes less : sedation , respiratory depression , hypotension than morphine.

Used in detoxification & maintenance of heroin abusers

Pentazocine

Agonist at KAPPA & antagonist at MU Receptors

Given orally or parentrally Has a short duration of action Less potent , less euphoric than

morphine High doses causes respiratory

depression

Adverse effects

Hallucination , nightmares , convulsions Increase Blood Pressure & Heart rate Precipitate withdrawal symptoms when given

to patients dependent on morphine CONTRAINDICATIONS With Morphine Heart diseases & Hypertension Epilepsy

OPIOID ANTAGONISTS

NALOXONE PURE ANTAGONIST AT MU RECEPTORS HAS a rapid onset of action (SECONDS ) &

Short duration of action (30-60min ) Is available for I.V. route Teatment of OPIOID overdoses ( ACUTE

TOXICITY )

NOTICE

Naloxone completely reverse respiratory depression produced by opioid over doses ,

Incompletely reverse their analgesic effects.

Naltrexone

Has a Long duration of action (10 HRS ) Given Orally Used clinically in : 1- Treatment of chronic Alcoholism 2-Control withdrawal symptoms of addicts 3- Reduce craving for alcohol in chronic

alcoholics

OPIOID ANTAGONISTS

In normal individual do not produce any effect.

IN dependent individual Precipitate withdrawal symptoms

NO Tolerance TO Their Antagonistic action NO withdrawal symptoms When Withdrawn

After Chronic Use