Narcotic analgesicsNarcotic analgesics►Definition:Definition: substance, whether endogenous substance, whether endogenous

or synthetic, that produces morphine-like or synthetic, that produces morphine-like effects that are blocked by antagonists such as effects that are blocked by antagonists such as naloxone. naloxone.

Receptors:Receptors:

Mu:Mu: all opioid effects and ADR except dysphoria all opioid effects and ADR except dysphoria

Delta and kappa receptorsDelta and kappa receptors

MOA:MOA:- Decrease adenyl cyclase & cAMP in brain- Decrease adenyl cyclase & cAMP in brain- Inhibit- Inhibit calcium channelscalcium channels in pre -synaptic in pre -synaptic

neuronsneurons inhibit pain neurotransmitters inhibit pain neurotransmitters releaserelease

- Stimulate - Stimulate K-channelsK-channels in post-synaptic neurons in post-synaptic neurons hyper-polarizationhyper-polarization

Pharmacological actionsPharmacological actions►1. Central effects (CNS):1. Central effects (CNS): ► I) Depressant effectsI) Depressant effects

a. a. Analgesia:Analgesia: without loss of consciousness without loss of consciousness by:by:

1.1. Inhibiting pain neurotransmitters release .Inhibiting pain neurotransmitters release .

2.2. ModifyingModifying emotionalemotional reactions to pain reactions to pain ((Euphoria)Euphoria)

b. b. Sedation:Sedation:

c. c. Respiration:Respiration: Resp. depression Resp. depression

d. d. Depress coughDepress cough center: center:

e. e. Hormones:Hormones: decrease dopamine, CRH, ACTH, decrease dopamine, CRH, ACTH, cortisol, LH, FSH & Testosterone cortisol, LH, FSH & Testosterone

f.f. Depress VMC:Depress VMC: in large doses in large doses hypotension hypotension

► II) Stimulatory effectsII) Stimulatory effects

1.1. Oculomotor nucleus Oculomotor nucleus pin-pointed pupil pin-pointed pupil

2.2. CTZ: CTZ: Nausea, vomiting Nausea, vomiting

3.3. Pituitary hormones: Pituitary hormones: Stimulates release Stimulates release ofof GH, prolactin GH, prolactin and ADHand ADH

4.4. Cardiac center: Cardiac center: bradycardia bradycardia►2. Peripheral effects: 2. Peripheral effects: ►1.1. CVS: CVS:►A.A. HeartHeart:: bradycardia bradycardia. (central and . (central and

direct)direct)►B. B. B.V:B.V: vasodilatationvasodilatation hypotension hypotension - Dilate cerebral BV - Dilate cerebral BV ONLYONLY when Resp when Resp

depressiondepression CO2 accumulation CO2 accumulation VD VD

► 2. Peripheral effects: 2. Peripheral effects: ► 2.2. GIT GIT:: SpasmogenicSpasmogenic► Constipation through:Constipation through:1. Decrease CNS perception of sensory stimuli for defecation.1. Decrease CNS perception of sensory stimuli for defecation.2. Increase in tone in sphincters, 2. Increase in tone in sphincters, decreasedecrease propulsivepropulsive

contractions contractions 3. Decrease in the3. Decrease in the GIT secretions. GIT secretions. ► 3. 3. Urinary system:Urinary system:-Oliguria due to: increase ADH release + hypotension + -Oliguria due to: increase ADH release + hypotension +

increase tone of ureter and the vesical sphincter.increase tone of ureter and the vesical sphincter. ► 4. 4. Uterus & fetusUterus & fetus:: Is it a good analgesic forIs it a good analgesic for labor labor

pain?pain?- Delay labor due to decrease pain sensation & spasm in - Delay labor due to decrease pain sensation & spasm in

uterine musclesuterine muscles-Pass placental barrier & BBB & suppress fetal respiration-Pass placental barrier & BBB & suppress fetal respiration-Less conjugated in fetus-Less conjugated in fetus higher blood level higher blood level► 5. 5. Immune system:Immune system: Suppress immune system Suppress immune system infection infection► 6.6. Skin:Skin: increase histamine release increase histamine release itching, urticaria, itching, urticaria,

Effects of morphine

PharmacokineticsPharmacokinetics►A. Absorption:A. Absorption: Well absorbed from all sites. In Well absorbed from all sites. In

shock there is less absorption from S.C. and I.M. shock there is less absorption from S.C. and I.M. ►B. Distribution:B. Distribution:

1. Highly lipid soluble drugs e.g. 1. Highly lipid soluble drugs e.g. HeroinHeroinare are concentrated in highly perfused organsconcentrated in highly perfused organs "brain""brain" & accumulate in fat on prolonged administration& accumulate in fat on prolonged administration

2. Crosses2. Crosses the placenta, less with tramadol & the placenta, less with tramadol & pethidinepethidine

C. Metabolism: C. Metabolism: extensiveextensive first pass first pass metabolismmetabolism so oral dose is much higher than so oral dose is much higher than parenteral. parenteral.

- It is - It is conjugatedconjugated with with Glucoronic AcidGlucoronic Acid 2 2 metabolites:metabolites:

M3-G M3-G convulsions, M6-G (more active). convulsions, M6-G (more active).

►D. Excretion: mainly renalD. Excretion: mainly renalPolar metabolites & small amount of free Polar metabolites & small amount of free

drug are excreted in urine. Renal drug are excreted in urine. Renal impairmentimpairment decrease excretion decrease excretion toxicity. toxicity.

►Tolerance:Tolerance: after 2-3 w of continuous after 2-3 w of continuous intake, need increase in dose up to 35 intake, need increase in dose up to 35 folds.folds.

1. 1. MarkedMarked tolerance to tolerance to the depressant the depressant effectseffects

2. 2. NoNo tolerance totolerance to antagonistic antagonistic oror stimulant effectsstimulant effects EXCEPTEXCEPT emetic & emetic & antidiuretic.antidiuretic.

3. There is3. There is cross tolerancecross tolerance to different to different opiates acting on same receptors.opiates acting on same receptors.

DependenceDependence►Physical & psychogenic dependencePhysical & psychogenic dependence►Sudden stopSudden stop Withdrawal syndromeWithdrawal syndrome

Adverse effectsAdverse effects►11. CNS:. CNS: Respiratory depression +Respiratory depression + dependencedependence►2. GIT:2. GIT: Nausea, vomiting, constipation & colic. Nausea, vomiting, constipation & colic.►3. B.V: 3. B.V: intracranial tension + Hypotensionintracranial tension + Hypotension 4. Muscles spasm:4. Muscles spasm: Urinary retention, increase Urinary retention, increase

biliary and renal colic & prolongation of labor. biliary and renal colic & prolongation of labor. ► 5. Histamine release5. Histamine release:: Itching, urticaria & Itching, urticaria &

bronchospasm. bronchospasm.

Therapeutic uses of OpioidsTherapeutic uses of Opioids►1. 1. TTT of painTTT of pain►2. 2. Acute left ventricular failureAcute left ventricular failure

and pulmonary edema.and pulmonary edema. ►3.3. Anesthesia (adjuvant) Anesthesia (adjuvant)►4.4. Anti-diarrheal: Anti-diarrheal: diphenoxylatediphenoxylate

►5.5. Cough: Cough: codeine.codeine.

Contraindications & Contraindications & precautionsprecautions►(Explain WHY for each one)(Explain WHY for each one)► 1. bronchial asthma1. bronchial asthma► 2. Head injury.2. Head injury. ► 3. Reduced blood volume3. Reduced blood volume (Induce (Induce

hypotension)hypotension)► 4. Myxoedema & Addison's disease4. Myxoedema & Addison's disease (prolong and (prolong and

exacerbate response to opioids). exacerbate response to opioids). ► 5. Advanced hepatic & renal diseases.5. Advanced hepatic & renal diseases. ► 6. During pregnancy or delivery 6. During pregnancy or delivery ► 7. Prostate hypertrophy.7. Prostate hypertrophy. 8. Biliary & renal colic.8. Biliary & renal colic.

► 9. Undiagnosed acute abdominal pain. 9. Undiagnosed acute abdominal pain.

Types of opioid analgesicsTypes of opioid analgesics►A. Pure agonists:A. Pure agonists: high affinity for high affinity for mu mu

receptors and low for kappa and delta. They receptors and low for kappa and delta. They include: include: Morphine:Morphine:

►Meperidine (pethidine)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:Methadone: It is mainly used to It is mainly used to relieve the relieve the

withdrawal symptomswithdrawal symptoms of morphine or of morphine or heroinheroin

Types of opioid analgesicsTypes of opioid analgesics►B. Mixed agonists-antagonists:B. Mixed agonists-antagonists: . Agonist at . Agonist at -receptors, antagonists at mu. -receptors, antagonists at mu. . They. They excitation, dysphoria excitation, dysphoria

&hallucinations, less Resp depression&hallucinations, less Resp depressionC. Opioid antagonistsC. Opioid antagonists►Naloxone: Naloxone: IV, 1h duration used in IV, 1h duration used in

Opioid overdoseOpioid overdose►Naltrexone: Naltrexone: Oral, 48hOral, 48h duration, used in duration, used in ►Maintenance Maintenance programs in treating programs in treating

addiction, alcoholism addiction, alcoholism