opioids

Question 1

opiate vs opioid vs narcotic

Answer 1

opiate: a compound that is structurally related to products found in opium, morphine codeine

opioid: any agent regardless of structure that has functional and pharmacological properties of an opiate
(endogenous opiods: naturally occuring ligands for opiod receptors)

Narcotic: a drug that produces a sleep like state, may or may not be analgesic, includes opiods and some other abused drugs

Question 2

endogenous opioid peptides

Answer 2

endorphins (POMC precursor): beta endorphin in hypothalamus and nucleus tractus solitarius, also in anterior pituitary, co released with ACTH during stress

Enkephalins (precursor- proenkephalin), leucine and methionine enkephalins have a wide CNS distribution especially in interneurons (esp those involved in pain pathway). Peripheral sites include adrenal medulla, nerve plexuses and exocrine glands of stomach and intestine

Dynorphins (precursor: prodynorphin): dynorphin A colocalized with vasopressin in magnocellular cells of hypothalamus and posterior pituitary, shorter dynorphins have wide CNS distribution, some are associated with pain pathways esp in sp cd

Question 3

measurement of endogenous opioids

Answer 3

plasma opioid peptides reflect release from secretory systems such as the pituitary and adrenals (do not reflect neuraxial release)

Conversely levels of these peptides in brain sp cd and CSF arise from neuraxial systems and do not from peripheral systems

Question 4

opioid receptors

Answer 4

Mu (supraspinal and spinal analgesia, slowed GI transit, modulation of hormone release, many other effects)

Delta (supraspinal and spinal analgesia) modulation of hormone and neurotransmitter release)

Kappa (supraspinal and spinal analgesia, psychotomimetic effects, slowed GI transit)

Question 5

opioid receptor distribution

Answer 5

wide distribution in brain and periphery: neuronal cell soma and axon terminals, macrophage cell types, astrocytes, enteric nervous systems

Question 6

clinical pharmacology of opioid drugs

Answer 6

analgesia, cough suppression, anidiarrheal/constipation, respiratory depression, peripheral vasodilation, reduced peripheral resistance, inhibition of baroreceptor reflexes, nausea, pupillary constriction, sedation, euphoria, endocrine effects, increased biliary pressure

Question 7

pain pathway

Answer 7

noxious stimuli activate nociceptor-pain receptors, A delta fibers mediate sharp localized pain to dorsal horn of sp cd (somatic pain, lamina I glutamate

C fibers mediate dull diffuse or achiching pain, visceral or neuropathinc pain, lamina II glutamate or substance P

2nd order neurons in spinothalamic tract–> thalamus, limbic system, somatosensory and association cortex (emotional cortex)

Descending path: Periaqueductal gray (midbrain) and rostro-ventral medulla to dorsal horn (via dosolateral funiculus), release NE, 5HT, enkephalin, and inhibit aactivity of ascending pain pathways

Question 8

mechanism of mu opioid receptors (MOR) induced analgesia

Answer 8

supraspinal- disinhibition of periaqueductal gray output neurons

spinal cord- pre and post synaptic effects on ascending pathway

peripheral- specific to inflammatory pain, normalizes hyperalesia

Question 9

cough suppression

Answer 9

direct actions on medullary cough center, may not be mediated by opioid receptors, Codeine and hydrocodone

Stimulation of mechno or chemo receptors (throat/respiratory passages)–> cough center in medulla–> efferent transmission to diaphragm, intercostal muscles and lung

independent of respiratory depression

Respiratory depression is the most serious side effect of opioids, mechanisms (decreased sensitivity of brainstem chemoreceptors to CO2, direct depressent effect on rhthym , increase chest wall rigidity (with higher doses such as those used in anesthetic induction) can have interactions with other CNS depressants

Question 10

antidiarrheal/constipation

Answer 10

opioid receptors are densely distributed in enteric neurons in the myenteric and submucosal plexi and on variety of secretory cells, opioids decrease gastric emptying

Question 11

peripheral vasodilation, reduced peripheral resistance, inhibition of baroreceptors

Answer 11

CV effects may be minimal when pt is supine, when supine pts assume heads-up position, orthostatic hypotension and fainting may occur

Mechanism: release of histamine from mast cells (fentanyl and sufentanil have much less effect on histamine) blunting of reflex vasoconstriction by increased Pco2

Question 12

nausea opioids

Answer 12

direct stimulation of chemoreceptor trigger zone (CTZ) in area postrema

Question 13

miosis opiods

Answer 13

disinhibition of edinger westphal output neurons (inhibition of local GABAergic interneurons disinhibits output neurons)

Question 14

sedation and euphoria

Answer 14

sedation- drowsiness and cognitive impairment, can augement respiratory depression, likely due to general CNS inhibition

Euphoria: Primarily mediated by mesolimbic circuit. Mu opioid receptors (MORs) on GABA interneurons in VTA disinhibit DA neurons, MORs on GABA medium spiny neurons in nucleus accumbens (NAc)

Question 15

Endocrine effects: anterior pituitary

Answer 15

males-reduction of cortisol, testosterone and gonadotropins

females- sames as males also reduction of luteinizing hormone (LH) and follicle stimulating hormone (FSH)
Mechanism thought to involve both hypothalamic effect (reduced GnRH and CRF) and pituitary effect (direct inhibition of pituicytes)
minimal effect on thyrotropin

prolactin: plasma prolactin elevated by opioids, DA released from tuberoinfundibular neurons inhibits prolactin release from pituitary lactotrope cells (opioids inhibit dopamine release by presynaptic mu opioid receptors)

Question 16

endocrine effects: posterior pituitary antidiuretic hormone and oxytocin

Answer 16

ADH reduced by kappa receptor agonists, oxytocin reduced by kappa receptor agonists,

agents such as morphine may yield a hypotension secondary to histamine release –> promoted ADH

Question 17

bilirary pressure

Answer 17

increases opioids supress inhibitory innervation of sphincter of Oddi, this effect exacerbates pain pts with biliary colic

Question 18

parmacokinetics of opioids

Answer 18

absorption: oral absorbtion and bioavailability varies by compound (poor for morphine and naloxone (1st pass),good for methadone. Rectal absorption is adequeate, transdermal for some highly lipophillic opiods, onset of action related to lipophilicity
distribution: all opioids bind to plasma proteins with varying affinity, rapidly leave the blood compartment and localize in highest concentration in highly perfused tissues, adipose tissue

Question 19

metabolism of morphine like compounds and non morphine like

Answer 19

many converted to polar metabolites that can be excitatory

non morphine like: hepatic oxidative metabolism is primary route- decreased renal function or those receiving high doses

Question 20

excretion of opioid

Answer 20

polar metabolites including glucuronide conjugates of opioid analgesics (morphine in urine as M3G)
small amounts of unchanged drug may also be found in urine, in pt with renal impairment,

Question 21

morphine

Answer 21

the prototype opioid, mu agonist, low oral to parenteral potency, duration of analgesia: 4-5 hours

heroin- diacetyl morphine, more lipophilic than morphine, high abuse potential

hydromorphone super potent

Question 22

opioid agonists– structurally related to morphine

Answer 22

codeine- for mild pain. morphine like efficacy is not achievable at any dose of codeine, some codeine is metabolized to morphine, often used in combo with NSAID

oxycodone and hydrocodone: for moderate to sever pain, available as sustained release oral preparation, major abuse problem, often used in combo with NSAID

Question 23

opioid agonists– structurally distinct to morphine

Answer 23

methadone- equivalent efficacy to morphine, good oral available, long duration of action used in treatment of opioid abuse and chronic pain

meperidine: a phenylpiperidine, shorter duration of analgesia than morphine, forms toxic metabolite, normeriperidine, that can accumulate with frequent use, interactions with MAO i

fentanyl- structurally related to meperidine, mu agonist, 100 X as potent as morphine, short acting 1-1.5 hrs, available in injectable form, transdermal patches and buccal soluble film break through pain

Question 24

other agonists

Answer 24

propoxyphene- withdrawn from USA market due to cardiac arrythmias

levorphanol- affinity at the MOR, 5HT/NE reuptake, NMDA receptor antagonist, rapid onset, modest duration of analgesia

tramadol: weak mu agonist, blocks NE and 5HT uptake, used for mild to moderate pain

etorphine, carfentanil- super potent, used in large animal tranquilizer darts, increasing street drug

Question 25

mixed action agonist/antagonist

Answer 25

buprenorphine: partial mu agonist, very potent compared to morphine, used to treat moderate to severe pain. A transdermal patch is also available, oral bup + naloxone to treat opioid dependence (Sub oxone)
nalbuphine: similar in efficacy and potentcy to morphine, lille euphoria and low abuse potential, can precipitate withdrawal in opioid dependent patients, available only by injection

Question 26

opioid antagonists

Answer 26

naloxone- high affinity for mu receptors, much greater activity parenterally, short duration, treats opioid overdoses, can be combined with opioids to decrease abuse, component of (SUBoxone)

naltrexone- long oral alf life, alcoholism and opioid addiction

Question 27

the 2 faces of naloxone

Answer 27

overdose treatment- parenternally

drug diversion- added to oral sublingual to prevent euphoria,

Question 28

tolerance- of opioids

Answer 28

rapid- nausea and vomiting

more gradual- analgesia, euphoria, respiratory depression, endocrine

little or none- miosis, constipation

Question 29

functional effects of acute and chronic opioid receptor activation

Answer 29

desensitization - acute tolerance, min to hrs
tolerance- days to weeks
dependancep during the tolerance
addiction/substance use disorders- behavioral pattern dependence=/addiction

Question 30

desensitization

Answer 30

probably mediated by receptor phosphorylation then internaliztion (mu and delta show rapid agonist-induced internalization, Beta arrestin dependent endocytosis, agonist-dependent, etorphine and enkephalins: rapid internalization, morphine: no significant rapid

and or G protein

Question 31

tolerance and dependence

Answer 31

tolerance- right shift in dose curve, surmountable with higher doses reversible with removal of drug, incomplete cross-tolerance

dependance- state of adaptation, revealed by drug withdrawal or antagonist treatment, withdrawal produces opposite symptoms of acute exposure somatomotor and autonomic outflow increased (hyperalgesia, hyperthermia, pupillary dilation
Aversion