Narcotic analgesics ► Definition: substance, whether endogenous or synthetic, that produces morphine-like effects that are blocked by antagonists such as naloxone. Receptors: Mu: all opioid effects and ADR except dysphoria Delta and kappa receptors MOA: - Decrease adenyl cyclase & cAMP in brain - Inhibit calcium channels in pre -synaptic neurons  inhibit pain neurotransmitters release - Stimulate K-channels in post-synaptic neurons  hyper-polarization

Pharmacological actions ► 1. Central effects (CNS): ► I) Depressant effects a. Analgesia: without loss of consciousness by: 1. Inhibiting pain neurotransmitters release. 2. Modifying emotional reactions to pain (Euphoria) b. Sedation: c. Respiration:  Resp. depression d. Depress cough center: e. Hormones: decrease dopamine, CRH, ACTH, cortisol, LH, FSH & Testosterone f. Depress VMC: in large doses  hypotension

► II) Stimulatory effects 1. Oculomotor nucleus  pin-pointed pupil 2. CTZ: Nausea, vomiting 3. Pituitary hormones: Stimulates release of GH, prolactin and ADH 4. Cardiac center: bradycardia ► 2. Peripheral effects: ► 1. CVS: ► A. Heart: bradycardia. (central and direct) ► B. B.V: vasodilatation  hypotension - Dilate cerebral BV ONLY when Resp depression  CO2 accumulation  VD - Dilate cerebral BV ONLY when Resp depression  CO2 accumulation  VD

► 2. Peripheral effects: ► 2. GIT: Spasmogenic ► Constipation through: 1. Decrease CNS perception of sensory stimuli for defecation. 2. Increase in tone in sphincters, decrease propulsive contractions 3. Decrease in the GIT secretions. ► 3. Urinary system: -Oliguria due to: increase ADH release + hypotension + increase tone of ureter and the vesical sphincter. ► 4. Uterus & fetus: Is it a good analgesic for labor pain? - Delay labor due to decrease pain sensation & spasm in uterine muscles -Pass placental barrier & BBB & suppress fetal respiration -Less conjugated in fetus  higher blood level ► 5. Immune system: Suppress immune system  infection ► 6. Skin: increase histamine release  itching, urticaria,

Effects of morphine

Pharmacokinetics ► A. Absorption: Well absorbed from all sites. In shock there is less absorption from S.C. and I.M. ► B. Distribution: 1. Highly lipid soluble drugs e.g. Heroinare concentrated in highly perfused organs "brain" & accumulate in fat on prolonged administration 2. Crosses the placenta, less with tramadol & pethidine C. Metabolism: extensive first pass metabolism so oral dose is much higher than parenteral. - It is conjugated with Glucoronic Acid  2 metabolites: M3-G  convulsions, M6-G (more active).

► D. Excretion: mainly renal Polar metabolites & small amount of free drug are excreted in urine. Renal impairment  decrease excretion  toxicity. ► Tolerance: after 2-3 w of continuous intake, need increase in dose up to 35 folds. 1. Marked tolerance to the depressant effects 2. No tolerance to antagonistic or stimulant effects EXCEPT emetic & antidiuretic. 3. There is cross tolerance to different opiates acting on same receptors.

Dependence ► Physical & psychogenic dependence ► Sudden stop  Withdrawal syndrome Adverse effects ► 1. CNS: Respiratory depression + dependence ► 2. GIT: Nausea, vomiting, constipation & colic. ► 3. B.V: intracranial tension + Hypotension  4. Muscles spasm: Urinary retention, increase biliary and renal colic & prolongation of labor. ► 5. Histamine release: Itching, urticaria & bronchospasm.

Therapeutic uses of Opioids ► 1. TTT of pain ► 2. Acute left ventricular failure and pulmonary edema. ► 3. Anesthesia (adjuvant) ► 4. Anti-diarrheal: diphenoxylate ► 5. Cough: codeine.

Contraindications & precautions ► (Explain WHY for each one) ► 1. bronchial asthma ► 2. Head injury. ► 3. Reduced blood volume (Induce hypotension) ► 4. Myxoedema & Addison's disease (prolong and exacerbate response to opioids). ► 5. Advanced hepatic & renal diseases. ► 6. During pregnancy or delivery ► 7. Prostate hypertrophy. 8. Biliary & renal colic. ► 9. Undiagnosed acute abdominal pain.

Types of opioid analgesics ► A. Pure agonists: high affinity for mu receptors and low for kappa and delta. They include: Morphine: ► Meperidine (pethidine) ► ► a. Less analgesic, less effect on cough or resp. depression and not delay labor. b. Has atropine & anti-H1 like action  no miosis, less constipation or urine retention, effective in colic ► Methadone: It is mainly used to relieve the withdrawal symptoms of morphine or heroin It is mainly used to relieve the withdrawal symptoms of morphine or heroin

Types of opioid analgesics ► B. Mixed agonists-antagonists:. Agonist at  -receptors, antagonists at mu.. They  excitation, dysphoria &hallucinations, less Resp depression C. Opioid antagonists ► Naloxone: IV, 1h duration used in Opioid overdose ► Naltrexone: Oral, 48h duration, used in ► Maintenance programs in treating addiction, alcoholism