M3L2

NARCOSIS

• Sources: Papaver spp.

NARCOSIS

Stupor and insensibility

Stupor

state of unconsciousness

Morphine

• P. somniferum

Thebaine

• P. bracteatum

NARCOTIC ANALGESIC

• Mixed action → activation of opioid receptors (, , receptors)

NARCOTIC ANALGESIC

• Mimicry (agonist)

NARCOTIC ANALGESIC

• Enhance release of opioid peptides:

  • Endorphins

  • Endomorphins

  • Dynorphins

  • Enkephalins

Opioid

painkillers

Endogenous Opioid Peptides

• natural painkillers

Proenkephalin

Precursor of Enkephalins

Met-enkephalin, Leu-enkephalin

Key peptides of Enkephalins

Delta > Mu

Receptor Preference of Enkephalins

Enkephalins

Pain modulation, mood regulation

Pro-opiomelanocortin

Precursor of Endorphins

β-endorphin, α-endorphin

Key Peptides of Endorphins

Mu

Receptor Preference of Endorphins

Endorphins

Pain relief, stress control

Endorphins

Euphoric Endorphin

Prodynorphin

Precursor of Dynorphins

Dynorphin A, Dynorphin B

Key Peptides of Dynorphins

Kappa

Receptor Preference of Dynorphins

Dynorphins

Mood regulation, stress response

Endomorphin- 1, Endomorphin-2

Key Peptides of Endomorphins

Mu

Receptor Preference of Endomorphins

Endomorphins

Potent analgesic effects

Endomorphins

Super Endorphins

Endomorphins

strongest natural painkillers

Mu (M,μ) receptor

responsible for majority of analgesic effec

Kappa (K,k) receptor

provides additional analgesia in women

Delta receptor (Δ,δ)

• responsible for spinal analgesia

Peripheral effects of Narcotics

• CVS: Bradycardia (except Meperidine),

• venodilation

• Biliary tract: contraction (except Meperidine)

• GIT: constipation

• Uterine muscles: Tocolysis

• Mast cells: Anaphylactoid reaction = pruritus

• Neuroendocrine

  • Stimulate release of ADH, prolactin, and somatotropin

  • Inhibit the release of luteinizing hormone

  • Modulate the immune system

Central Effects of Narcotics

• Analgesia

• Euphoria

• Addiction

• Sedation

• Miosis

• Cough suppression

• Respiratory depression

• Convulsion

• Truncal rigidity – an intensification of tone in the trunk muscles

• Nausea and vomiting

Somatic

musculoskeletal pain

Somatic

• Tx NSAID

Visceral

 internal organ pain

Visceral

• Tx Narcotics

Neuropathic

nerve pain

Neuropathic

• Tx Anticonvulsant

Tramadol

Tx for Mild Visceral pain

Codeine and company

Tx for Moderate Visceral Pain

Morphine and friends

Tx for Severe Visceral Pain

Morphine

Mgt of Acute Pulmonary Edema

Fentanyl IV

Anesthetic adjuncts (general anesthesia)

Diphenoxylate, Loperamide

Antidiarrheals

Loperamide

usually used as low doses; if used in high doses, it induces narcotic effects

Dextromethorphan

Antitussive

Toxic Effecs of Narcotics

• Respiratory depression - greatest threat

Epinephrine

Tx for Anaphylactoid reaction

Naloxone

Antidote for Opioid Toxicity

Triad of Toxicity

• Pinpoint pupils (Myosis)

• Respiratory Depression

• Comatose

Contraindications of Narcotics

• Pregnancy = baby becomes addicted, may have withdrawal symptoms

• Pt with head trauma (high intracranial pressure = accumulation of blood to the brain)

• Do not combine a partial agonist with a full agonist, it becomes antagonist

• One of the effects of Opioids:

  • Cerebral Vasodilation ( blood flow, ICP)

Opiates

Natural source

Opioids

semi-synthetic, synthetic source

MORPHINE

Reference standard as analgesic

MORPHINE

• Poor oral bioavailability (25-30%)

HEROIN

Diacetylmorphine, diamorphine

HEROIN

Equal efficacy compared to morphine

HEROIN

• Recreational drug; drug of abuse

HEROIN

• From morphine (with the addition of Acetic Anhydride & heat)

APOMORPHINE

Similar structure with morphine but not analgesic as it has no affinity to mu and any opioid receptor

APOMORPHINE

Dopamine reuptake inhibitor = enhance dopamine effect

APOMORPHINE

Mgt of Parkinsonism

Semisynthetic morphine derivatives

Ex. Hydromorphone, Oxymorphone

Semisynthetic morphine derivatives

8-12 times more potent than morphine = require lesser dose = still same level of effect

Semisynthetic codeine derivatives

• Ex. Hydrocodone, Oxycodone

Semisynthetic codeine derivatives

8-12 times more potent than codeine

METHADONE

Same efficacy with morphine

METHADONE

Advantage: good oral BA, long DOA = less rapid development of tolerance

METHADONE

Use: to wean off morphine and heroin addicts – withdrawal is not a problem

MEPERIDINE

• Pethidine (Demerol)

MEPERIDINE

No cardiac and biliary effect = no bradycardia & no contraction of capillary tract

MEPERIDINE

• Used for acute pain only

Normeperidine

Toxic Metabolite of Meperidine

LEVORPHANOL

5-7x more potent than morphine

LEVORPHANOL

D-isomer of levorphanol: Dextromethorphan - antitussive

FENTANYL

100x more potent than morphine

FENTANYL

Usually administered with droperidol

FENTANYL

IV administered general anesthetic = induced opioid combination

Loperamide, Diphenoxylate, Difenoxin

Antidiarrheals

Loperamide

without addiction

Lomotil (Loperamide)

•  formerly Atropine + Diphenoxylate (Paired with atropine to prevent the addictive properties of Diphenoxylate)

Diphenoxylate

• with addiction → Remedy: co administer with Atropine

Difenoxin

Metabolite of diphenoxylate

Dextromethorphan, Levopropoxyphene

• Antitussive

Dextromethorphan

Free of addictive properties, less constipating than codeine

Levopropoxyphene

• Devoid of opioid effects though can cause sedation

Tramadol

For mild pain, weak mu agonist

Pentazocine

Partial Kappa agonist

kappa agonist

Pentazocine when alone

mu antagonist

Penazocine with full agonist

STRONG FULL MU RECEPTOR AGONIST

Used in severe pain management

STRONG FULL MU RECEPTOR AGONIST

Morphine, Heroin, Hydromorphone, Oxymorphone, Methadone, Meperidine, Levorphanol, Fentanyl

Used for mild to moderate pain relief

MILD TO MODERATE FULL AGONIST

Codeine, Hydrocodone, Oxycodone, Tramadol

PARTIAL AGONIST

Dual interaction with full agonists (D/I)

PARTIAL AGONIST

Nalbuphine, Butorphanol, Buprenorphine, Pentazocine

Used as antidotes for narcotic poisoning

FULL ANTAGONISTS

Naloxone (Famously used), Naltrexone, Nalorphine, Nalmefene, Levallorphan

Full Agonists

Strongly activate opioid receptors for pain relief