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