Lecture 72 - Pharmacology of Opiate Drugs

Question 1

OPIUM CONTAINS TWO TYPES OF ALKALOIDS

Answer 1

Phenanthrenes: Morphine (10%), Codeine (0.5%), Thebaine (0.2%)
Benzylisoquinolines: Noscapine (6%), Papaverine (1%)
Opiates are only those opioids that are naturally occurring

Question 2

STRUCTURE ACTIVITY RELATIONSHIPS (SAR) OF PHENANTHRENES

Answer 2

3 position substitutions ether or ester produces decreased potency – codeine
6 position increases activity – hydromorphone or hydrocodone (from codeine)
14 position OH has increased potency – oxycodone
N-allyl give antagonist (or mixed antagonists) – naloxone or naltrexone

Question 3

THE HUMAN GENOME CONTAINS SEVERAL GENES ENCODING ENDOGENOUS OPIOIDS

Answer 3

Peptides active endogenously
Large precursor proteins are cleaved into more opioid subtype selective peptides
Degree of redundancy
1. Pro-opiomelanocortin: beta-endorphin –> Mu opioid
2. Preproenkephalin: Leu-Enkephalin –> delta opioid, Met-Enkephalin = mu and delta
3. Preprodynorphin: dynorphin –> kappa opioid
4. Nociceptin/Orphanin FQ

Question 4

TYPES OF OPIOID RECEPTORS

Answer 4

G protein-coupled receptor: Family A – peptide receptors; Gi/o-coupled (inhibition of cAMP production); Open GIRK potassium channels; Close calcium channels
Mu (M – morphine): Endogenous opioid = endorphin
Kappa (K – ketocyclazocine): Endogenous opioid = dynorphin
Delta (D – deferens -> where identified): Endogenous opioid = enkephalin
Nociceptin, orphanin FQ receptor: Endogenous opioid = nociceptin
Sigma receptors – not an opioid receptor

Question 5

OPIOID RECEPTOR SIGNAL TRANSDUCTION

Answer 5

Presynaptic = Inhibit calcium channel (Gi) decrease in neurotransmitter release
Postsynaptic = activate GIRK channel (Gβγ) Efflux of K+ => hyperpolarization

Question 6

THE MU OPIOID RECEPTOR

Answer 6

Beta-endorphins (endogenous morphine): Pro-opiomelanocortin (POMC); Component of runners high
Therapeutic use: Analgesia - Not as effective for chronic pain; Cancer pain, palliative, PCA
(patient-controlled analgesia)
Sedation
Antitussive: Suppression of cough center in the medulla oblongata - Codeine (mechanism unclear though)

Question 7

OPIOID INDUCED SIDE EFFECT – ARE MOSTLY ON-TARGET EFFECTS!!

Answer 7

Respiratory depression: Brain stem; pre-Bötzinger complex in the ventrolateral medulla
Constipation: GI tract
Pruritus (itch): Side effect, not allergic response
Addiction
Urinary retention: opioid-induced ADH release
Nausea/vomiting: Chemoreceptor trigger zone - medulla
Miosis: Oculomotor nerve (PAG); Not mepiridine (has anti-cholinergic effects)

Question 8

KAPPA OPIOID RECEPTOR

Answer 8

Dynorphins natural ligand: Preprodynorphin
Activation is dysphoric, aversive
Potential use for treatment of addiction –> Reduce dopamine release
Counterbalance mu opioid receptor effects

Question 9

DELTA OPIOID RECEPTOR

Answer 9

Enkephalins are natural ligand: Preproenkephalin
More dynamic expression: Intracellular, “externalized” upon chronic stimuli
Role in hypoxia/ischemia/stroke: Hibernation release of enkephalin like opioid
Reduce anxiety
Reduce depression
Treat alcoholism
Relief hyperalgesia, chronic pain
Side effect: seizures!
No FDA-approved delta opioids

Question 10

Opioid site of action

Answer 10

ventral tegmental area –> nucleus accumbens

Question 11

DEPRESSANTS CAN CAUSE DOPAMINE RELEASE JUST LIKE STIMULANTS

Answer 11

1. Opioid binds mu receptor
2. Gi signaling inhibits neurotransmitter release
3. Less GABA to activate GABAA
4. Less inhibition of dopamine neuron activity
5. Increase dopamine release
6. Increased activation of dopamine receptors

Question 12

ADMINISTRATION ROUTES AND PHARMACOKINETICS OF OPIOIDS

Answer 12

Intravenous
Intra-axial: intrathecal, epidural
Intra muscular
Oral
Topical/transdermal

Question 13

PHARMACOKINETICS OF MORPHINE/PHENANTHRENES

Answer 13

Metabolism: Readily absorbed; First pass metabolism - Morphine bioavailability 25% Hepatic: CYP2D6, CYP3A4; Genetic differences; Elimination T1/2 increased with liver disease
Glucuronidation at 3’ and 6’ position
Morphine-6-glucuronide (M6G) - Still potent Excretion: Glomerular filtration; 90% excreted in 24h

Question 14

SOME OPIOID METABOLITES ARE STILL ACTIVE

Answer 14

Heroin, codeine, tramadol ≈ prodrugs
Heroin+ codeine form morphine; tramadol forms O-desmethyltramadol
Fentanyl and methadone do not produce active metabolites
Onset/duration influenced by lipophilicity: Morphine: low lipophilicity, slower passage across BBB, prolonged duration of action; Fentanyl: high lipophilicity, rapid onset, short duration

Question 15

CYP3A4 (FOUR) -> MAKES OPIOIDS STARTING WITH

Answer 15

NOR

Question 16

CYP2D6 METABOLIZERS – GENES IMPACT OPIOID MANAGEMENT

Answer 16

UM phenotype is of high relevance worldwide
* Frequency of 40% in North Africa
* Only 3% in Europe
* Up to 50% higher plasma concentrations of morphine than EM (when given codeine)
* Higher incidence of adverse effects
PM phenotype more common in Caucasians (10%)
* No therapeutic effect from codeine (pro-drug, metabolized to morphine)
* Same incidence of adverse effects

Question 17

FENTANYL IS A VERY POTENT OPIOID

Answer 17

~100x potent over morphine
~50x potent over heroin
Used for palliative care: Breakthrough pain

Question 18

MANY OPIOIDS ARE USED SURROUNDING (PRE/PERI/POST) A HOSPITAL PROCEDURE

Answer 18

All listed opioids are schedule II unless indicated
Agonists:
Sufentanil, Remifentanil, Alfentanil: Anesthesia/sedation; Breakdown by plasma esterases due to ester linkage
Fentanyl (i.v., patch, lollipop)
Hydromorphone (Dilaudid), oxymorphone (Opana): No opioid-active metabolites; i.v., oral liquid - PCA
Morphine (IV, po – PCA): Covered by medicare => preferred over oxycontin; Extended Release (MScontin); Long acting, lower ‘rush’, M6G contribution to pain relief. Risk for abuse if i.v. injected at once
Hydrocodone: (Zohydro [ER], Lortab/Vicodin/Norco = + acetaminophen)
Oxycodone: (Oxycontin, Percocet = + acetaminophen)

Question 19

NON-PHENANTHRENE OPIOIDS ARE A SPECIAL SUBCLASS OF OPIOIDS

Answer 19

tramadol, tapentadol
meperidine

Question 20

Tramadol (Ultram), Tapentadol (Nucynta)

Answer 20

Mild opiate analgesic
Has SNRI properties: 5HT/NE reuptake inhibitor, stimulate 5HT release
Management of mild neuropathic pain.
Painkiller used when you don’t want to prescribe a stronger opioid
Schedule IV (Ultram)

Question 21

Meperidine (Demerol)

Answer 21

Used to treat rigors (shivering)
Has toxic metabolite normeperidine: Metabolite is devoid of analgesic activity; Neurotoxic => nervousness, tremors, muscle twitches, and seizures
Renally excreted: Dangerous in patients with decreased renal function (accumulation); Not recommended without good justification

Question 22

CERTAIN OPIOIDS CAN BLOCK NMDA RECEPTORS

Answer 22

Methadone (non phenanthrene)
Primarily used for opioid dependence
Long duration of action/long half life (15-60hrs)/fat solubility
Prolonged QTc – unwanted effect
NMDA antagonist
Chronic pain
NMDA is an ion channel glutamate receptor that is important for conduction of pain signals, block it, block pain signal coming in

Question 23

CLINICALLY USED OPIOIDS (NON-ANALGESIC) - cough/antitussive

Answer 23

Cough/antitussive
Usually codeine (schedule II): Schedule V in certain formulations
Dextromethorphan: Enantiomer of levomethorphan (opioid); Limited opioid activity (not scheduled); At high doses acts as SSRI, NMDA antagonist

Question 24

CLINICALLY USED OPIOIDS (NON-ANALGESIC) - antidiarrheal

Answer 24

Anti-diarrheal
Diphenoxylate with atropine (Lomotil®): Schedule V
Loperamide (Imodium®): Strong P-glycoprotein substrate – low BBB penetration; Schedule V/decontrolled=OTC
Eluxadoline (Viberzi®): Irritable bowel syndrome with diarrhea; Mu/kappa agonist, delta antagonist; Enteric nervous system localization; Schedule IV

Question 25

SOME OPIOIDS ACT AT MOR AND KOR AND ARE USED FOR MODERATE PAIN

Answer 25

pentazocine and butorphanol
nalbuphine
buprenorphine

Question 26

Pentazocine (Talwin®) and Butorphanol (Stadol®, sch. IV)

Answer 26

κ agonist, partial agonist/antagonism at μ Parenterally administered
Side Effects: Less dysphoria, hallucinations, Increase in BP, HR

Question 27

Nalbuphine (Nubain®, sch. IV)

Answer 27

Full agonist at κ, antagonist at μ
Antagonism produces withdrawal
Parenterally (i.v., i.m.) administered

Question 28

Buprenorphine (Buprenex®, Subutex®, sch. III)

Answer 28

Partial μ agonist, weak κ agonist and δ antagonist
Primary use in opioid replacement therapy

Question 29

PREVENTIVE AND ACUTE MANAGEMENT OF ILEUS AND CONSTIPATION

Answer 29

Senna: Irritates colon – cause fluid secretion/colonic contraction
Polyethylene glycol (Miralax): Stool softener – Osmotic increase in GI water content
Dioctyl sodium sulfosuccinate/docusate: Stool softener, Peristalsis >400 mg/day

Question 30

THERAPEUTIC TOLERANCE AND SIDE EFFECT TOLERANCE

Answer 30

Opioid tolerance: Analgesic effects, Nausea, Urinary retention, Respiratory depression - Biggest risk of death in withdrawn patients/users, Euphoria
Limited/no tolerance: Constipation, Itch, Miosis

Question 31

TREATMENTS FOR OPIOID DEPENDENCE – MEDICATION-ASSISTED TREATMENT (MAT)/SUBSTITUTION THERAPY

Answer 31

methadone
buprenorphine
naltrexone
narcan

Question 32

METHADONE, THE FULL AGONIST

Answer 32

Full mu opioid receptor agonist: Cross tolerance
Provide relief from withdrawal: ≥potency than morphine, oxy. dilaudid
‘Slow’ acting (2-4 hours)
Slow pharmacokinetics: Accumulates with repeated dose; Elimination half-life (8-50hrs)
Racemic mixture: (+) = NMDA antagonist; Structurally different from morphine

Question 33

BUPRENORPHINE, THE PARTIAL AGONIST

Answer 33

Mu opioid receptor partial agonist: Ceiling effect; Blocks full agonist effect (heroin, oxycodone) - Antagonist, Use 4hrs after last heroin use; Provides some activation - Agonist, Less withdrawal
Subutex: Abuse potential
Suboxone (4:1 bup: Nx): Partially blocks agonist effects when taken i.v.

Question 34

NALTREXONE, THE ANTAGONIST

Answer 34

Naltrexone (Vivitrol): Intramuscular injection; Extended release; Once monthly - PO administered =Revia, Daily dose; Decent oral bioavailability; Medium half-life (4 hrs); Will cause withdrawal; Works better if patient has been drug free for 1 month or more

Question 35

THE OPIOID ANTAGONISTS NALOXONE AND NALTREXONE ARE NOT INTERCHANGEABLE

Answer 35

Naloxone: I.V. or intranasal administered; limited oral bioavailability (1-2%); Rapid onset (1-2 minutes); Short half-life (30-90 minutes)
Naltrexone: Decent oral bioavailability; PO administered; Medium half-life (4 hrs) - longer word than naloxone

Question 36

NARCAN - 1 SHOT IS OFTEN NOT ENOUGH

Answer 36

Naloxone (Narcan): I.V. or intranasal administered; Limited oral bioavailability (1-2%); Rapid onset (1-2 minutes); Short half-life (30-90 minutes)
Give multiple shots to avoid return of respiratory depression
Presence of fentanyl and other synthetic opioids means even more doses: Repeat every 2-5 minutes if not conscious
Causes strong withdrawal

Question 37

NEONATAL ABSTINENCE SYNDROME IS DRUG DEPENDENT

Answer 37

Symptoms: Some hospitals may have Newborn Abstinence Scores to help the diagnosis
– Tremors
– Yawning
– Poor Feeding
– Sweating
Onset
– Symptoms may begin 24 to 48hrs after birth or as late as 5 to 10 days
Heroin and other opiates, including methadone: Cause serious withdrawal in the baby. Some symptoms can last as long as 4 to 6 months. Seizures may also occur in babies born to methadone users; Opioids can also be present in breast milk

Question 38

TREATING NEONATAL ABSTINENCE SYNDROME - nonpharmacological

Answer 38

• Swaddling
  – Hypercaloric Formula
  – Frequent Feedings
  – Observation à Sleep, temperature, weight gain/loss, and change in symptoms
  – Rehydration à IV fluids if dehydration is severe

Question 39

TREATING NEONATAL ABSTINENCE SYNDROME - pharmacological

Answer 39

• Morphine Sulfate –> Oral Morphine diluted to 0.4 mg/ml
  – Sublingual Buprenorphine
  – Methadone –> 0.05 to 0.1 mg/kg/dose every 6 hours
  – Morphine and buprenorphine linked with shorter hospital stay than methadone
  – Clonidine may also be useful