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Neuro Pharmacology > Opioid Analgesics > Flashcards

Opioid Analgesics Flashcards

1
Q

What is an Opiate?

A

Compounds structurally related to opium products.

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2
Q

What is an Opioid?

A
  1. An agent w/ functional and pharmacological properties of an opiate.
  2. Opium-like compound that binds to one of three receptors.
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3
Q

What is a narcotic?

A

Substances that blunt the senses.

Legal Term: Harrison Narcotic Act 1914.

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4
Q

Opioid Analgesics compared to non-opioid:

A
  1. Produce Tolerance
  2. Produce psychological & physical dependence.
  3. Greater efficacy for pain.
  4. Good for Cardiac, Visceral pain.
  5. Site of action is central
  6. Have different side effect profiles
  7. Are structurally quite homegeneous.
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5
Q

What do Endorphins contain?

A

endogenous opioid peptide

31 aa, containing met-enkephalin

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6
Q

What do Enkephalins contain?

A

Endogenous opioid peptide

5 aa, leu- & met-enkephalin

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7
Q

What do Dynorphins contain?

A

Endogenous opioid peptide

13-17 aa, containing leu-enkephalin.

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8
Q

What is the distribution of opioid receptors?

A
  1. Brain
    - Spinal Cord
    - Enteric nervous system (lining of esophagus, stomach, small intestine and colon)
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9
Q

What are the 4 opioid peptide precursors?

A
  1. Proorphanin
  2. Prodynorphin
  3. Proenkephalin
  4. POMC
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10
Q

What are the endogenous ligands of mu1 supraspinal and mu2 spinal receptors subtypes?

A
  1. Beta endorphin
    more than met- and leu-enkephalin endomorhpin-1
  2. Dynorphin A more than B
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11
Q

What are agonists for the mu1 and mu2 opioid receptor subtypes?

A
  1. Morphine

2. Other pure agonists.

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12
Q

What effects do agonizing mu1 receptor subtypes cause?

A
  1. Supraspinal analgesia
  2. Sedation
  3. Hypothermia?
  4. Euphoria
  5. Physical dependence
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13
Q

What effects do agonizing mu2 receptor subtype cause?

A
  1. Spinal analgesia
  2. Sedation
  3. Respiratory depression
  4. GI tract decrease transit.
  5. Bradycardia
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14
Q

What are the endogenous ligands for delta receptor subtypes?

A
  1. met- and leu-enkephalin

2. Beta endorphin

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15
Q

What are agonists of the delta receptor subtype?

A
  1. Sufentanil (weak)
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16
Q

How many kinds of delta receptor subtypes are there?

A

2

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17
Q

What effects do agonizing delta receptor subtypes cause?

A
  1. Analgesia
  2. Anti-depressant effects
    Less than mu agonists
  3. GI
  4. Dependence
  5. Respiratory depression
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18
Q

What are the endogenous ligands of kappa receptor subtypes?

A
  1. Dynorphin A & B.
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19
Q

What are agonists of the kappa receptor subtype?

A
  1. Butorphanol more than other

2. Partial agonists/antagonists.

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20
Q

How many kinds of kappa receptor subtypes are there?

A

3

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21
Q

What effects do agonizing kappa receptor subtypes cause?

A
  1. Spinal (k1) and supra spinal (k3) analgesia
  2. Miosis?
  3. Physical dependence
  4. GI tract decrease transit
  5. Aversive behavioral effects including
    - Psychotomimesis/Dysphoria
  6. Sedation
  7. Diuresis
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22
Q

What are common actions of all opioid receptor subtypes?

A
  1. Each coupled to Gi/G0
  2. Galpha protiens
  3. Inhibit adenylate cyclase
  4. Negatively coupled to Voltage dependent Ca channels
    - L and N type (reduce opening)
  5. Promote K current (efflux) hyperpolarization.
  6. Activation of PKC and PLCbeta
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23
Q

What are the opioid classifications by source?

A
  1. Natural (morphine & codeine)
  2. Semi-synthetic
  3. Synthetic
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24
Q

What are the opioid classifications by structure?

A
  1. Phenanthrenes
  2. Phenylpiperidines
  3. Diphenylheptane
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25
Q

What are examples of Phenanthrenes?

A
  1. Buprenorphine, Butorphanol, Codeine, Dezocine
  2. Hydrocodone, Hydromorphone, levorphanol, morphine
  3. Nalbuphine, oxycodone, oxymorphone.
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26
Q

What are examples of Phenylpiperidines?

A
  1. Alfentanil
  2. Fentanyl
  3. Mepiridine
  4. Sufentanil
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27
Q

What are examples of Diphenylheptanes?

A
  1. Methadone.
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28
Q

What are the roles of endorphin?

A
  1. Placebo
  2. Acupuncture
  3. Labor/Delivery
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29
Q

What are the properties of Morphine?

A

Agonist of mu receptor subtype

  1. standard dose = 10mg IM for 70kg adult.
  2. PO F 0.25, due to 1st pass metabolism
  3. Rectal F 0.25
  4. SC F 0.5
  5. IM
    - Good if good blood flow through the muscle
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30
Q

What is the Distribution of Morphine?

A
  1. Everywhere including fetus!

2. PPB 35%

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31
Q

What is the metabolism of Morphine?

A
  1. half life 2 hours

2. Role of morphine-6-glucuronide in effects.

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32
Q

What are the important metabolites of morphine?

A
  1. M3G

2. M6G

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33
Q

What percent of Morphine is metabolized into M3G and through what?

A
  1. 90%

2. UGT2B7

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34
Q

What percent of Morphine is metabolized into M6G and through what?

A
  1. 10%
  2. UGT2B7
    - Effective metabolite
    - M6G trapped in the brain
    - 100X higher affinity for receptor.
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35
Q

What are the CNS actions of Morphine type opioids?

A
  1. Euphoria - rapid tolerance
  2. Drive satiation
  3. Sedation
  4. Analgesia (sensory modality specific)
    - Increase pain threshold
    - Change perception of pain.
  5. Respiratory depression
    - RR decreases by 33%
  6. cough suppression (antitussive)
  7. Hypothermia
  8. N&V
  9. Pupillary reaction
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36
Q

How do morphine type opioids change the perception of pain?

A
  1. Act on thalamus & modulate connections to limbic system.
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37
Q

What is the main cause of OD death?

A

Respiratory Depression

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38
Q

What are the mechanisms for respiratory depression of morphine type opioids?

A
  1. Depress neurogenic drive (dorsal & ventral medullary respiratory neurons)
  2. Decrease response to increased CO2
    - Medullary chemoreceptors
    - Aortic body chemoreceptors
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39
Q

When should Morphine type opioids be used with caution?

A

In pts w/ compromised respiratory function, sleep apnea, COPD, asthma, emphysema.

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40
Q

What is the mechanism of cough suppression for morphine like opioids?

A
  1. d-isomers of opioids: Codeine, hydrocodone, dextromethorphan
  2. Analgesic activity is in I-isomer
  3. Medullary cough center (cough receptor in throat reflex to this)
  4. 25% of analgesic dose.
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41
Q

What actions do d-isomers of morphine like opioids lack?

A
  1. Respiratory depression
  2. Analgesia
  3. Tolerance
  4. Drowsiness
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42
Q

What is an inappropriate use of morphine like opioids?

A

Productive cough.

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43
Q

What pupillary reaction is involved in actions of morphine like opioids?

A
  1. Miosis - constriction
  2. Oculomotor nerve, edinger-westphal nucleus
  3. General lack of tolerance
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44
Q

How does N&V with morphine like opioids?

A
  1. Biphasic chemoreceptor trigger zone stimulation followed by blockade.
  2. Role of vestibular stimulation
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45
Q

How do you deal with N&V b/c of morphine?

A
  1. Reduce physical activity
  2. Dosage schedule
  3. Anti-emetics: transdermal scopolamine, promethazine.
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46
Q

What actions do Morphine type opioids have on the CV system?

A
  1. little effect on HR, and CO
  2. Decreased workload due to decreased left ventricular diastolic pressure, cardiac work & decrease venous return.
    (NOT produced by partial agonist-antagonists)
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47
Q

When is the action of morphine type opioids used regarding the CV system?

A

MI, acute pulmonary edema, CHF.

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48
Q

What other cardio effects do morphine type opioids have?

A
  1. Orthostatic hypotension.
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49
Q

What is the difference b/w opioid induced histamine release and Type 1 IgE mediated hypersensitivity?

A
  1. Non-allergic (histamine release)
  2. Drug allergy (on re-challenge)
    - very rare
    - IgE
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50
Q

What is seen with opioid induced histamine release?

A
  1. Pruritis
  2. Flushing
  3. Hives
  4. Hypotension
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51
Q

What is seen with Type 1 IgE mediated opioid hypersensitivity?

A
  1. Hives
  2. Bronchospasm
  3. Respiratory distress
  4. Laryngeal edema
  5. Hypotension
  6. Acute cardiovascular collapse
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52
Q

What effective dose of morphine type opioids produce smooth muscle effects?

A

Increased tone

less than analgesic dose: 2-4 mg, codeine 15-30 mg

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53
Q

What effects do morphine type opioids have on GI?

A
  1. Decreased GI motility
    - Constipation
    - Inhibits peristalsis but does NOT stop mixing action (cramping)
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54
Q

What are the treatments for GI issues with morphine?

A

one or more of the following:

  1. Stool Softener (emollient lubricant: docusate)
  2. Stimulant cathartic (Senna, Bisacodyl, Cascara)
  3. Saline cathartic
  4. PEG 3350
  5. Opioid receptor antagonists.
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55
Q

Increasing the tone of smooth muscle by morphine like opioids causes what in the biliary tract?

A
  1. Contraction of Sphincter of Oddi

2. Increased pressure in gallbladder.

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56
Q

Increasing the tone of smooth muscle by morphine like opioids cause what in the urinary bladder?

A
  1. Contraction of Detrusor muscle and trigone muscle

2. Urinary retention.

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57
Q

Why is Morphine used as an analgesic in palliative care?

A
  1. Prevent and relieve suffering and to support the best possible quality of life for patients and their families, including effective pain management.
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58
Q

When is morphine used as an analgesic in obstetrics?

A
  1. Epidural
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59
Q

Why is morphine used as an analgesic for MI?

A
  1. Decrease Cardiac work, sedation.
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60
Q

What is the possible negative effect in using morphine for analgesic effects during pre- and post-surgery?

A
  1. May prolong recovery, due to activation of microglia.
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61
Q

What kind of pain is exhibited in Fibromyalgia?

A
  1. Chronic non-malignant pain, fatigue, sleep problems.
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62
Q

What is the treatment for acute low back pain?

A

Less than 2 weeks

  1. NOT opioids due to physical dependence
  2. NSAIDs, APAP, skeletal muscle relaxants, physical therapy.
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63
Q

What is the treatment for chronic low back pain?

A

More than 3 months, due to spinal abnormalities, disk herneation.

  1. NOT opioids
    - Risk of physical dependence
    - Opioids increase time out of work and medical expense.
  2. Exercise to strengthen muscles, manipulation.
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64
Q

What is the WHO 3-step analgesic ladder?

A

Step 1: Mild to Moderate Pain
-Non-opioid +/- adjuvant agent
Step 2: Mild to Moderate Pain or Pain uncontrolled after step 1.
- Short acting opioid as required +/- non-opioid ATC +/- adjuvant agent.
Step 3: Moderate to Severe Pain or Uncontrolled after step 2.
-Sustained release/long acting opioid ATC or continuous infusion +/- short acting opioid as required +/- non opioid +/- adjuvant therapy.

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65
Q

What are the long acting oral dosage forms?

A
  1. Kadian
  2. MS Contin
  3. Oramorph SR
  4. Avinza
    - immediate and ER beads in capsule.
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66
Q

Where should opioids be injected in the spinal cord?

A
  1. Into Cauda Equina
    - Spinal nerves present but not solid cord
    - Less risk of SCI
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67
Q

When is intraspinal administration used for chronic pain?

A
  1. Typically when standard treatments fail.
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68
Q

What two drugs are FDA approved for intrathecal administration for chronic pain?

A
  1. Morphine & Ziconotide
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69
Q

What is Ziconotide?

A

NON-Opioid

  1. N-Type voltage sensitive Ca channel blocker that blocks neurotransmitter release from presynaptic primary nociceptive afferent nerve terminals
  2. Approved for chronic pain in patients who do not tolerate or respond to other treatments.
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70
Q

What is Codeine?

A

3-methylmorphine

  1. Morphine pro-drug
  2. Oral administration (more complete than morphine)
  3. CYP2D6 metabolized
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71
Q

What are the uses of codeine?

A

Mild-moderate pain (65 mg)
Antitussive (15-20 mg)

Abuse potential LOW.

72
Q

What kind of opioid is Heroin?

A

Semi-Synthetic

3,6-diacetylmorphine.

73
Q

What kind of opioid is Hydrocodone?

A

Semi-synthetic opioid

74
Q

What is the metabolism of Hydrocodone?

A
  1. O-demethylation by CYP2D6 to Hydromorphone
    - Contributing to effects; influenced by level of CYP.
  2. N-Demethylation by CYP3A4 to Norhydrocodone
    - weak, active metabolite; basis of drug interaction.
75
Q

What is Hydrocodone used for?

A
  1. Antitussive, Analgesic - Most effective w/ NSAID, ASA or APAP.
76
Q

What is the most prescribed drug in the US?

A

Hydrocodone (w/ APAP)

77
Q

What is the FDA warning about Hydrocodone?

A

Warned against use in children less than 6

78
Q

What is Obredon?

A

Hydrocodone + Guaifenesin

79
Q

What are characteristics of Hydromorphone (Dilaudid)?

A
  1. 5-10X morphine potency (when potent + small volume needed)
  2. More soluble than morphine
  3. Produces less N&V and histamine release than morphine.
  4. Available as parenteral, rectal and short-acting oral formulations.
80
Q

What are the characterisitcs of Oxycodone?

A
  1. 1/2 as effective orally as parenterally
    - comparable efficacy parenterally as morphine
    - 1.5X more potent than oral morphine.
81
Q

What is Oxycontin?

A

12 hour duration of action

-Black Box warning about abuse.

82
Q

What is Oxecta?

A

Immediate release oral tablet that uses AVERSION Technology.

83
Q

To reduce Oxycontin abuse what was it reformulated with?

A
  1. More binders so does not powder well, becomes gummy when wet, difficult to snort - Labeled OP.
84
Q

What are characteristics of Oxymorphone?

A
  1. Parenteral use
    - Potency 10X of morphine
  2. Rectal suppository (Numorphan)
  3. Oral immediate release 5&10 mg tablets (Opana)
  4. Oral extended release 5,10,20&40 mg tablets (Opana ER)
85
Q

What is the oral bioavailability of Oxymorphone?

A
  1. 10%

2. Increased 38-50% with food.

86
Q

What can happen to someone who crushes and injects 40mg Opana ER tablet?

A

IV injection can produce thrombotic thombocytopenic purpura.

  • Formation of blood clots in small vessels that can produce kidney failure & death.
87
Q

What are the characteristics of Methadone (Dolophine)?

A
  1. Qualitatively similar and equipotent to morphine parenterally.
  2. Additional MOA
  3. Orally Effective (F=0.8-0.9) 1/2 as effective orally than IV
  4. SYNTHETIC OPIOID
88
Q

What is the additional MOA of Methadone?

A

Inhibition of N-methyl-D-aspartate (NMDA) receptors.

89
Q

What is the distribution of methadone?

A
  1. Lipophilic, can accumulate in chronic dosing.

2. Half life 55hr in acute, 24-36 in chronic dosing, due to auto-induction of metabolism (interpatient variability)

90
Q

What is the duration of analgesic effect of Methadone?

A
  1. Short, requiring 3X daily dosing

2. Poor correlation between blood levels and dose.

91
Q

What are the uses of Methadone?

A
  1. Analgesic
  2. Opioid Detox
  3. Opioid maintenance of physical dependence.
92
Q

What are the characteristics of Fentanyl?

A
  1. 75-100X Morphine Potency

2. SYNTHETIC OPIOID

93
Q

What is the duration of action after IV admin of fentanyl?

A
  1. Fast Onset, Short 30 min
  2. Due to redistribution out of the brain
  3. t1/2 2.5-12 hours.
94
Q

How is Fentanyl metabolized?

95
Q

What are uses of Fentanyl?

A
  1. Pre-anesthetic medication
  2. Anesthetic supplement
  3. For minor surgery
  4. Procedures such as bronchoscopy, colonoscopy, reduction of fractures, outpatient general anesthesia.
96
Q

What formulation of Fentanyl is used for injection?

A

Fentanyl Citrate (Sublimaze)

97
Q

How is Fentanyl used to treat Neurolepanalgesia?

A

Combined w/ Droperidol as a neuroleptic

Innovar - Droperidol 2.5 mg/ml & Fentanyl 0.05 mg/ml

98
Q

Why is fentanyl able to be used as a patch?

A
  1. Based on Low M.W., High Potency, Lipophilicity
  2. Releasing 25mcg/10cm2/h
  3. Blood levels reach a plateau in 12-14 hrs. (MAX EFF)
  4. Heat can increase release rate.
99
Q

What is Ionsys?

A
  1. A patient controlled fentanyl ionotrophic transdermal system delivering 40 mcg fentanyl (as Cl)/ activation over 10 min for up to 6/h for 24 hr.
  2. Applied to skin, low-intensity electric field facilitates drug absorption through the skin.
100
Q

What is the Fentanyl Lozenge on a stick used for?

A
  1. Fentanyl Oralet - pre-medicate children.
  2. Actiq - for breakthrough cancer pain.

Rapid absorption through oral mucosa and slower from the GI tract.

101
Q

What is the Fentanyl Buccal/Transmucosal tablet used for?

A

(Fentora)

  1. Breakthrough pain
  2. 25% absorbed through buccal membrane
  3. 25% from the GI tract.
  4. As a buccal soluble film (onsolis) for breakthrough pain.
102
Q

What is Sufentanyl?

A
  1. 7X potency and 1/2 duration of action of fentanyl

2. Synthetic

103
Q

What is Alfentanil?

A
  1. 1/4 as potent, more rapid acting and shorter duration of action than fentanyl.
  2. Synthetic
104
Q

What is Remifentanil?

A
  1. Esterase metabolized

2. Biological half life 3-5 min.

105
Q

What is the dose of Meperidine compared to Morphine?

A
  1. 1/3-1/4 as potent orally as parenterally

2. Parenterally 80-100 mg = 10mg morphine

106
Q

What is the onset of action of Meperidine compared to Morphine?

107
Q

What is the Duration of Action of Meperidine compared to Morphine?

A
  1. 2-4hrs Vs. 4-5hrs
108
Q

What is seen less of with Meperidine use?

A

Less smooth muscle spasmogenic activity, including constipation.

109
Q

What is the active metabolite of Meperidine and what can it cause?

A
  1. Normeperidine

2. Can accumulate to produce CNS toxicity, so should not be used in high doses for chronic conditions.

110
Q

What are uses for Meperidine?

A
  1. Treatment of Moderate Acute pain 24-48hrs.
111
Q

How is MPTP toxicity caused?

A
  1. Meperidine like designer drug MPTP is converted to MPP by MAO-B and causes ROS to form in Dopaminergic neurons, and increased catecholamines that cause apoptosis.
112
Q

What are examples of Meperidine like Antidiarrheals?

A
  1. Diphenoxylate

2. Loperamide

113
Q

What is Diphenoxylate?

A

Peripherally acting smooth muscle spasmogenic that poorly enters the CNS

+ Atropin = Lomotil

114
Q

What is Loperamide?

A

Low GI absorption and poor blood-brain barrier permeability.

115
Q

What is Tramadol (Ultram)?

A

A partial mu (weak) pure agonist.

116
Q

What is the additional MOA of Tramadol?

A

Inhibits NE & 5-HT reuptake.

117
Q

what is Tramadol with APAP called?

118
Q

What is 100 mg Tramadol equivalent regarding ASA & Codeine?

A

650 mg ASA

60 mg Codeine

119
Q

What is the metabolism of Tramadol?

A
  1. CYP2D6 to an active metabolite
    - O-desmethyltramadol
  2. Higher affinity for mu receptors than tramadol; and partly metabolized by CYP3A4.
  3. CYP2D6 poor metabolizers have 20% higher serum tramadol and 40% lower metabolites.
120
Q

What are the side effects of Tramadol?

A
  1. Seizures
  2. Anaphylactoid reactions
  3. Hypoglycemia.
121
Q

What is Tapentadol?

A

A mu agonist

-Some structural similarity to tramadol

122
Q

What formulations of Tapentadol are available?

A
  1. Nycynta (immediate release)

2. Nycynta ER (has polyethylene oxide matrix that is resistant to crushing & immediate drug extraction.

123
Q

What is the additional MOA of Tapentadol?

A

Inhibits NE reuptake.

124
Q

What is Buprenorphine?

A

A partial mu agonists, kappa antagonist.

-20X morphine potency to produce equianalgesia

125
Q

What is the association between Buprenorphine and Respiratory Depression?

A

This agent and mixed agonist/antagonists show a maximal respiratory depression 2-3X therapeutic dose.

126
Q

What is Subutex?

A

Sublingual tablet used to treat opioid dependence.

CIII

127
Q

What is Suboxone?

A

Buprenorphine + Naloxone

CIII

128
Q

What is Bunavail?

A

Buccal Fil

Buprenorphine + Naloxone

129
Q

What are characteristics of Suboxone?

A
  1. Buprenorphine
    - Partial mu agonist/kappa antagonist
    - Reversibly binds to receptors
    - Maintains opioid dependence
  2. Naloxone
    - Full mu, kappa, delta receptor antagonist
    - Binds when agonist comes off receptor
    - NOT absorbed through mucosa in mouth or anywhere in GI.
130
Q

If Suboxone is taken as intended what will happen to the naloxone?

A

It will not be absorbed.

131
Q

If someone crushes or dissolves components of Suboxone what will happen.

A

Naloxone will be absorbed through parenteral route, which would put the user into withdrawal.

132
Q

What is Eluxadoline?

A

A partial mu agonist, kappa agonist, delta antagonist.

  1. For Diarrhea predominant irritable bowel syndrome
  2. Designed to reduce constipation that can occur w/ unopposed mu opioid receptor agonists.
133
Q

What do Mixed (kappa) agonist, (mu) antagonists do?

A
  1. Produce agonist action at kappa receptor and weak antagonist action at mu1 and mu2 receptors.
134
Q

What are general properties of Mixed (k) agonsit, (mu) antagonists?

A
  1. Maximal Efficacy Less than pure mu agonists
  2. Psychotomimesis (dose related)
  3. Respiratory Depression Increases to a plateau w/ dose escalation w/ partial agonist/antagonists vs. linear relationship w/ pure mu agonists.
  4. Smooth muscle contraction less than mu agonists
  5. Dependence potential less than mu agonists.
135
Q

What is Salvia Divinorum “magic mint”?

A

Hallucinogenic Plant

  1. used for divination and shamanism by Mazatecs
  2. Salvinorin A is the active component of S. divinorum.
  3. Kappa opioid receptor is the molecular target.
136
Q

What is Pentazocine?

A 
A mixed (k) agonists, (mu) antagonist. 
Talwin Nx tablet (Pentazocine + Naloxone)
137
Q

What is Butorphanol?

A

A mixed (k) agonist, (mu) antagonist

  1. Undergoes greater than 80% first pass metabolism in liver.
  2. Butorphanol tartrate for injection (Stadol) as a nasal spray (Stadol NS) avoids first pass metabolism.
  3. 1 spray (1mg), repeat 60-90 min if necessary, then q3-4 hrs.
138
Q

What drugs are there shared system REMS for?

A
  1. ER and Long-acting opioid analgesics in treatment of moderate to severe chronic pain.
  2. Transmucosal immediate release fentanyl
  3. Buprenorphine transmucosal products for opioid depnedence.
139
Q

What are the genetic factors influencing opioid response?

A
  1. Different mu receptor subtypes
    - Opioid receptor, mu1 has only one gene (OPRM), many splice variants in the human
    - An OPRM1 polymorphism: Asn40ASP
    - Risk of dependence
140
Q

What are the Age factors influencing opioid response?

A
  1. Very young have poor developed BBB
  2. Children have more water allowing hydrophillic drugs (morphine) to circulate more effectively and be elminated more slowly.
    - Premature infant 85% water half life 6-9hr
    - Adult 65% water half life 1.5-2hr
  3. Geriatrics have reduced pain sensitivity, cardiac and hepatic function.
141
Q

What are the Contraindications of opioid use?

A
  1. Hypersensitivity (allergy)
  2. Acute Bronchial Asthma
  3. Head Injury
  4. Higher risk of ADR in:
    - sleep apnea
    - Obese
    - Pulmonary disease
    - CHF
    - Renal Insufficiency w/ some opioids (morphine/Meperidine)
142
Q

Why is opioid use contraindicated in patients w/ head injury?

A
  1. Respiratory depression increases CO2 to produce cerebral vasodilation to increase intracranial pressure.
143
Q

What does drug interaction between opioids and other CNS depressants cause?

A
  1. Supra-additive respiratory depression.
144
Q

What is Naloxone?

A
  1. Pure Opioid Antagonist
  2. Not orally effective due to extensive first pass metabolism.
  3. half life 1 hr.
  4. Onset of Action 1-3 min
  5. Duration of action 1-4 hrs
  6. Typical Dose: 0.4-2mg IV.
145
Q

What is Nalmefene?

A

Pure opioid antagonist
Not orally absorbed
half life 11hr

146
Q

What is Naltrexone?

A
  1. Pure opioid antagonist
  2. Vivitrol -ER microspheres for IM injection
  3. Orally EFFECTIVE
  4. 5-40% reaches systemic circulation due to first pass.
  5. A metabolite (6-beta-naltexol) may provide activity.
  6. half life 10hr
  7. Duration of Action: can be days after 100mg BLOCKS heroin effects up to 72 hours.
147
Q

Therapuetic Uses of Opioid Antagonists?

A
  1. For known or suspected opioid overdose
  2. Reverses opioid-induced respiratory depression
  3. Discourage opioid abuse
  4. Treat ethanol dependence
  5. Potential problem in opioid-dependent person.
148
Q

What is the dose for opioid overdose?

A

0.04-2mg IV w/ repeat dosing, up to 10 mg

149
Q

How is naltrexone used to discourage opioid abuse?

A
  1. Three times weekly PO 100mg M&W, 150mg F.
150
Q

How does Naltrexone help ethanol dependence?

A
  1. Decreases ethanol-induced dopamine release in nucleus accumbens to reduce positive reinforcement effect.
151
Q

What is Naloxegol?

A
  1. Polyethylene glycol conjugate of naloxone.
  2. Peripherally Selective (not oral)
  3. Opioid induced consitbation w/ non-cancer pain. (12.5-25mg) to increase frequency of spontaneous bowel movements.
  4. DOES NOT alter analgesic response to opioid.
152
Q

What is Methyl Naltrexone?

A
  1. Given subcutaneously, induces a bowel movement within 30 min.
  2. For opioid-induced constipation in patients w/ advanced illness receiving palliative care.
153
Q

What is Alvimopan?

A
  1. Selective mu-opioid receptor antagonist
  2. For oral treatment of post-operative ileus after bowel resection. Oral F 6%
  3. Blocks mu-opioid receptors in GI tract but does not interfere w/ central analgesic effects of opioids.
154
Q

What are symptoms of intoxication of opioids?

A
  1. Euphoria, drive suppression
155
Q

What are signs of intoxication of opioids?

A
  1. CNS & Respiratory Depression:

2. Miosis, hypothermia, Decreased Bowel sounds.

156
Q

What is the Treatment of Opioid Overdose?

A
  1. Maintain respiration.

2. Reverse OD w/ an antagonist - MAY NEED TO REPEAT.

157
Q

What is considered opioid tolerance?

A
  1. To analgesia
  2. To CNS depression
  3. To Euphoria
  4. Degree of tolerance can be 20- 40-fold. Cross tolerance among pure agonists, not w/ mixed kappa agonist-mu antagonists.
  5. Not to pupillary constriction or increased smooth muscle tone.
158
Q

What is the mechanism of opioid tolerance?

A

Increase Adenylate cyclase, countering opioid-induced decreased cAMP.

159
Q

What is Physical Opioid Dependence?

A
  1. Begins w/ first dose

2. 50% of patients receiving therapeutic doses for 1-2 weeks have some physical dependence.

160
Q

What are Drugs to maintain opioid depnedence?

A
  1. Methadone CII
  2. Long half life enables prolonged receptor occupancy, preventing withdrawal and decreasing ability of other opioids to bind.
  3. Dose: adequate to maintain the depnedence Often 60-100mg/day
  4. Other effects: as all opioid mu agonists.
  5. Buprenorphine
161
Q

What are the goals of therapy for opioid addiction?

A
  1. Suppression of withdrawal symptoms
  2. Reduction of symptoms drug craving
  3. Reduce number of “use events”
  4. Disrupt opioid use disorder behaviors
  5. Reduction in criminal activity
  6. Successful return to workforce.
162
Q

What are Opioid Withdrawal symptoms?

A
  1. Anxiety, Restlessness
  2. Diarrhea, Increased Lacrimation
  3. Skeletal muscle contraction
  4. Piloerection.
163
Q

What are the opioid withdrawal approaches?

A
  1. Cold Turkey
  2. Methadone or Buprenorphine withdrawal
  3. Clonidine (Duraclon): to decrease excessive SNS activity.
164
Q

What are Adjuncts to Non-opioid and Opioid Analgesics?

A
  1. Caffeine
  2. Antidepressants
  3. Serotonin & NE reuptake inhibitors.
  4. Anticonvulsants
  5. Corticosteroids
165
Q

Why is Caffeine used as a co-analgesic?

A
  1. CNS stimulant
  2. Antagonist at all adenosine receptors
  3. A2 are vasodilators, antagonism - mild cerebrovasoconstriction.
  4. 65mg increase relative activity of analgesics 40% produces more rapid absorption of analgesics.
166
Q

Why are antidepressants used as a co-analgesic?

A
  1. Amitriptyline 75 mg/day (vs. antidepressant dose)
  2. MOAs: Na channel block, Inhibition of NE & 5-HT reuptake.
  • Venlafaxine
  • Duloxetine
167
Q

What anticonvulsants are used as adjunct therapy?

A

Carbamazepine, Phenytoin, Gabapentin

Dose: similar to epilepsy.

168
Q

Why is Hydroxyzine, and Phenothiazines used?

A
  1. Increase analgesic effect of NSAIDs & Opioids, Decrease N&V.
169
Q

What is the mechanistic flow of tissue injury evoked nociception?

A
  1. Tissue injury
  2. Local release of active factors
  3. Persistent activation/sensitization of Adelta/C fibers
  4. Activity in ascending pathways + spinal facilitation.
  5. Exaggerated output for given stimulus input.
  6. Ongoing pain + Hyperalgesia.
170
Q

What is the Mechanistic flow of nerve injury evoked nociception?

A
  1. Nerve injury.
  2. Peripheral nerve degeneration (neruoma)
  3. Spontaneous Afferent activity and spinal sensitization lead to spontaneous dysesthesias (shooting, burning)
  4. Spinal Sensitization and Abeta afferent fibers lead to allodynia (light touch hurts)
171
Q

What is neuropathic pain?

A
  1. Hyperalgesia to mechanical and thermal stimuli.

Allodynia: elicitation of pain by normally non-painful simtuls

172
Q

What are causes of Neuropathic pain?

A
  1. Diabetes: peripheral neruopathy
  2. Tic douloureaux (trigeminal neuralgia)
  3. Shingles: Vericella Zoster virus that causes chicken pox.
  4. Post-hepatic neuralgia
  5. Sciatica
  6. Phantom limb pain maybe.
173
Q

What are the mechanisms of neuropathic pain?

A
  1. Thought to include dysfunctional astrocytes and microglia in spinal cord dorsal horn that release inflammatory cytokines.
  2. Persistent activation of post-synaptic glutamate recetpors.
  3. Increased Ca release to increase NT release & pain.
  4. Some loss of descending inhibitory and GABA controls.
174
Q

What is Neuropathic Pain Pharmacotherapy?

A
  1. Not very responsive to opioids b/c damage to primary afferent nerve cause decreased expression of opioid receptors.
  2. Tricyclic antidepressants among most effective.
  3. Anti-epileptic
    - Gabapentin (Postherapetic neuralgia)
    - Pregabalin (Neuropathic pain assoicated w/ postherpetic neuralgia, diebtic neurpophaty, fibromyalgia)
175
Q

What are other pharmacotherapies for neuropathic pain?

A
  1. SSNRI reuptake inhibitor duloxetine (Cymbalta)
  2. Botulinum toxin
  3. Topical local anesthetics
  4. Topical counter-irritants (capsaicin)
  5. Anti-inflammatory agents
  6. Marijuana

Neuro Pharmacology (9 decks)

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