Opioid Analgesics Flashcards
1
Q
Opioid Analgesics drug list
A
2
Q
Definition . . .
- OPIATE
- OPIOID
- ANALGESIA
- HYPOALGESIA
- HYPERALGESIA
- ALLODYNIA
A
- OPIATE: compounds structurally related to products found in opium
- OPIOID: any agent that has the functional & pharmacological properties of an opiate
- ANALGESIA: without pain
- HYPOALGESIA: reduced pain perception induced by analgesics
- HYPERALGESIA: increased pain associated with mild noxious stimulus
- ALLODYNIA: pain evoked by non-noxious stimulus
3
Q
Definition:
- NARCOTIC
- ENDORPHIN
- NOCICEPTIVE PAIN
- NEUROPATHIC PAIN
- CHRONIC PAIN
A
NARCOTIC: agent that induces sleep (narcosis)
ENDORPHIN: endogenous opioid peptide
NOCICEPTIVE PAIN: involves pain receptors & transmission over intact nerves
NEUROPATHIC PAIN: caused by damaged neural structures
CHRONIC PAIN: pain that outlasts precipitating tissue injury
4
Q
Endogenous opioid peptides (general)
A
Endogenous opioids have the same pharmacological properties as exogenous opioids: 1) analgesia 2) blocked by naloxone
.
Synthesized by 4 precursors:
› Preproenkephalin: met-enkephalin, leu-enkephalin
› Preproopiomelanocortin (POMC): β-endorphin, ACTH, α- MSH, β-LPH
› Preprodynorphin: dynorphin A, dynorphin B, neoendorphin
› Preorphanin FQ (N/OFQ): orphanin, nocistatin, orphanin-2, endomorphin-1, endomorphin-2
.
- Each of these precursors is produced in a variety of brain areas and goes through different proteolytic processing
5
Q
pain or nociceptor
TWO COMPONENTS OF PAIN . . . and how
A
- Specific sensation: the perception, localization and discrimination of pain.
Experimental pain is acute, of short duration, and non-inflammatory such
as that associated with a surgical procedure.
Pathological pain is chronic and inflammatory such as that associated with healing
. - Reaction to the sensation: the subjective & psychological aspect. This is
related to the anxiety, fear, panic, and suffering associated with pain. This
response depends on the individual’s personality, psychological profile, and
previous experiences with pain.
.
Opioid analgesics OBTUND pain. Opioids raise the threshold for pain
perception and alter the affective pain response. No other senses are
affected
6
Q
The Pain Pathway
A
7
Q
Pain
- Integumental pain
- Visceral pain
A
- Integumental pain
› Dermis, mucosa, skeletal muscle, joints, headache, dysmenorrhea
› Controlled by NSAIDs which act locally at sites of inflammation to synthesis of prostaglandins and inhibit release of the algesic autacoid, bradykinin
› May be combined with narcotics (two different mechanisms)
. - Visceral pain
› Pain within body cavities (thorax and abdomen)
› Diffuse, hard to localize and referred to other sites
› Best treated with opioids with their main action on the spinal cord and upper CNS
.
NSAIDs are not as effective unless pain is associated with inflammation (concept is changing)
8
Q
Pain - tissue injury and inflammation
A
-Components of tissue injury such as 5-HT, histamine, bradykinins, prostaglandins, K+, H+ lower the pain threshold. They produce inflammation, allodynia, and hyperalgesia.
.
- Nonsteroidal Antiinflammatory Drugs (NSAIDS) act to inhibit cyclooxygenases (COX) thereby preventing prostaglandin production. Prostaglandins sensitize
neurons to pain stimuli.This is a peripheral mechanism of action.
.
- Local anesthetics inhibit axonal action potential propagation. This is a peripheral mechanism of action.
9
Q
Pain - nerve injury
A
- Substance P, glutamate & calcitonin gene-related peptide (GCRP) are neurotransmitters in the C afferents
- Neuropathic pain initiated by low-threshold sensory fibers (Aβ fibers, mechanoreceptors) i.e nerve trauma, chemotherapy, diabetes, post-herpetic neuralgia
- Neuropathic pain is not as responsive to analgesics as nociceptive pain.
10
Q
Pain and neurologic inflammation
A
11
Q
Supraspinal actions - opioids
A
12
Q
Spinal opiate action
A
13
Q
Spinal cord site of action
A
Continue
- Glutamate & Neuropeptides transmit pain signal in the dorsal horn of the spinal cord
- Presynaptic opioid receptors on primary afferents decrease the action potential induced Ca2+ influx which decreases Substance P and CGRP release. › Axoaxonic mechanism
- Postsynaptic opioid receptors increase K+ conductance which induces IPSP, hyperpolarization of the neuron and reduces pain neurotransmission
- Intrathecal or epidural opioids. Produce analgesia. Such analgesia is rapid in onset, long lasting, has few side effects, and no physical dependence
14
Q
Opioid peripheral action
A
- Direct application of high [opiate] can produce local-anesthesia type response that is NOT reversed by naloxone
- Peripheral sites under conditions of inflammation, where there is an increased terminal sensitivity leading to an exaggerated pain response, direct injection of opiate produces a localized “normalizing effect” on those exaggerated thresholds
- Descending NE projections act on alpha-2 receptors on primary C-fiber terminals to decrease the opening of voltage-gated calcium channel -> reduce entry of Ca2+, reduce neurotransmitter release (Substance P, glutamate, CGRP)
15
Q
Opioid Receptors . . . general
A
- 3 classes: MOR, DOR, KOR (µ, δ, κ)
- Virtually all clinically useful agonists target MOR
- All opioid receptors have 7 TM regions are G-protein coupled
. - Postsynaptic effects include
› Decreased adenylyl cyclase production
› Decreased neuronal inhibition by hyperpolarization (activation of receptor operated K+ channels)
. - Presynaptic effects include
› Inhibition of voltage sensitive Ca++ channels that decrease
neurotransmitter release
. - Ligands that bind specifically but have limited intrinsic activity are partial agonists (for MOR, i.e. buprenorphine)
16
Q
Opioid Receptors classification
A
17
Q
Opioid analgesics (general)
A
- Considered to act by a central mechanism. Although opioid receptors are located peripherally and local injection of opioids in inflamed tissue is analgesic, such analgesia is not reversed by naloxone.
. - Nociceptive Afferent Fibers
› C-fibers: nonmyelinated & slow conduction speed (Mediates dull burning pain)
› Aδ fibers: myelinated with rapid action potential conduction (High-threshold sensory afferents…Mediates sharp, well-localized pain)
18
Q
Morphine . . . general/ stucture
A
- Morphine is derived from opium, extract of the opium poppy papaver somniferum. Opium is a solid extract of the dried milky exudate of unripe seed capsules, contains 9-14% morphine
› Raises pain threshold @ spinal cord level
› Alters CNS perception of pain
. - Morphine (µ) agonists act on secondary ascending neurons to activate K+ channels, inducing an IPSP, thus reducing the excitation of neurons
19
Q
Tolerance and Cross tolerance . . . define all the diff type of tolerance
A
› Acute tolerance (desensitization): occurs within minutes of dose,
disappears parallel to metabolic clearance of drug
.
› Pharmacokinetic tolerance: less drug present at site of action
(hepatic enzyme induction will increase drug metabolism = metabolic tolerance)
.
› Pharmacodynamic tolerance: same amount of drug present at site of action, but response is reduced due to changes in receptors or mechanisms
.
› Cross tolerance: tolerance to most drugs within a class.
May be partial or incomplete
Opioid rotation
.
› Behavioral tolerance: individual compensates for decrease effect
.
› Innate tolerance: some individuals are less affected by the drug. G
Genetically predetermined
20
Q
Opioid dependence
- Physical dependence & cross-dependence
- Psychological dependence
A
1.) Physical dependence & cross-dependence
› Removal of drug from physically dependent person results in withdrawal/abstinence syndrome (Significant somatomotor & autonomic outflow (agitation, hyperalgesia, hypertension, diarrhea, mydriasis, dysphoria))
› Drugs that induce physical dependence are cross dependent to other drugs within the class
.
2.) Psychological dependence
› Patient feels effects of drug are necessary to maintain optimal state of well-being
› Does not imply pathology until drug use impairs functioning
› May occur without physical dependence or tolerance
› The basis for compulsive drug use and addiction
21
Q
Classification of opioid compound
A
22
Q
Pharmacological effects of opioids
A
23
Q
Pharmacological effects of opioids: Mood changes (general)
A
- Euphoria: sense of contentment and well-being
› Especially apparent when relief of pain accompanies administration
› µ agonists enhance DA release from neurons in Nucleus Accumbens to induce euphoria
› Separate mechanism from analgesia - Mental Clouding
› Drowsiness, lethargy, apathy (non-addictive type persons may experience
mental clouding that can be reported as dysphoric)
24
Q
Mood Alteration & euphoria
A
- Neural systems that mediate opioid reinforcement overlap with those involved in physical dependence and analgesia. The mesocorticolimbic DA system that
comes from the VTA & projects to the Nucleus Accumbens is pivotal in drug-induced reward and motivation. - Increased DA underlies a positive reward state
- In the NAc, MOR’s exist on postsynaptic GABAergic neurons.
- The reinforcing effects of opiates are mediated partly via inhibition of local GABAergic activity, which otherwise acts to inhibit DA outflow
25
Pharmacological effects of opioids
- May occur @ therapeutic doses
.
- Most common cause of death
Decreased response of brainstem respiratory neurons to CO2 (chemical drive)
Hypoxic response of the carotid sinus and aortic arch chemoreceptors are only affected at high doses
Hypoxic drive maintains respiration in opioid overdose; administration of O2 may further decrease respiration
.
› Bronchoconstriction can contribute to respiratory depression via histamine release
26
Pharmacological effects of opioids:
| respiratory depression
Administer with caution in cases of impaired pulmonary function
› Chronic bronchial asthma
› Chronic obstructive pulmonary disease (COPD)
› Other meds that cause respiratory depression
.
Respiratory depression and increased pCO2 cause:
› Cerebrovascular vasodilation
› Secondary elevation of CSF pressure
.
Can be exaggerated in the presence of head injury, other intracranial lesions or pre-existing increase in intracranial pressure. DO NOT USE.
27
Pharmacological effects of opioids:
respiratory depression
.
Other factors that may increase the risk of opiate-related respiratory depression at therapeutic doses:
› CNS depressants: general anesthetics, ethanol, bzd’s, sedative- hypnotics, opioid combinations
› Sleep: decreases in sensitivity of medullary center to CO2 and depressant effects of morphine are at least additive. Sleep apnea is risk factor for fatal-respiratory depression
› AGE
Newborns: if opioids are administered parenterally within 2-4 hours of
delivery, they are permeable to infant’s BBB
Elderly: reduced lung elasticity, chest wall stiffening, decreased vital
capacity
.
› Relief of pain: pain stimulates respiration-removal of pain will reduce
ventilatory drive
› Organ dysfunction: renal &/or hepatic dysfunction
28
Pharmacological effects of opioids:
| nausea and vomiting
Caused by direct stimulation of the CTZ for emesis in the area postrema of the medulla
All clinically useful agonists produce some degree of N/V
Nausea occurs in about 40% of ambulatory patients given analgesic doses
Vomiting occurs in about 15%
Opioid agonists produce an increase in vestibular sensitivity
29
Pharmacological effects of opioids:
| GI Effects
Constipation and antidiarrheal effect
› Affects intestinal smooth muscle to relieve diarrhea by Decreasing peristaltic gut motility Increasing tone (persistent contraction)
› Acts through peripheral opioid receptors
.
Constipation is resistant to tolerance and will delay passage of GI contents; may
also delay drug absorption
30
Pharmacological effects of opioids:
GI Effects
Opioid-Induced constipation (OIC) in adults with chronic opioid use
Naloxegol (Movantik)
Pegylated derivative of naloxone: doesn’t cross BBB and can reverse constipation produced by systemic opioid agonists
.
Relistor (Methylnaltrexone)
Selective µ antagonist
Quaternary amine: doesn’t cross BBB
tx of OIC in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient
31
Pharmacological effects of opioids:
GI Effects
.
Eluxadoline (Viberzi)
› Indicated for tx of irritable bowel syndrome with diarrhea (IBS-D)
› µ agonist, κ agonist, δ antagonist
› Warnings:
Spasms in muscle of digestive tract (sphincter of Oddi) which may cause new or worsening abdominal pain. Increased risk in patients w/o gallbladder
Pancreatitis - increased risk in patients who drink >3 alcoholic drinks per day
32
Pharmacological effects of opioids:
| Urinary tract
Inhibits urinary voiding reflex
.
Increases tone of the external sphincter
.
Water retention
› Increases ADH release by central mechanism
› Decreases bp (reduced glomerular filtration) results in water retention
› Catheterization may be required in severe cases, usually after spinal drug administration
.
Effect is through peripheral opioid receptors and can be reversed by peripherally acting antagonists
.
Tolerance develops
33
Pharmacological effects of opioids:
| Miosis
Stimulation of µ and κ receptors located in the Edinger-Westphal nucleus of the oculomotor nerve III.
Activates parasympathetic outflow – pupil constriction
.
HIGH DOSES of opioid agonists produce marked pinpoint pupils.
› While some tolerance to the miotic effect may develop, addicts with high circulating concentrations of opioids will continue to experience miosis
› Marked mydriasis will occur with the onset of asphyxia
› Does NOT develop with meperidine; tends to be a narcotic of choice for abuse by health care professionals
› Blocked/reversed by opioid antagonists or atropine
34
Pharmacological effects of opioids:
| Histamine release
Morphine causes mast cell degranulation with release of histamine causing urticaria, itching, diaphoresis and vasodilation.
May precipitate bronchospasm in asthmatics
Reversed by antihistamines but not naloxone
Itching is readily seen with morphine and meperidine, but to a much lesser extent
with oxymorphone, methadone, fentanyl or sufentanil.
35
Pharmacological effects of opioids:
neuroendocrine effect
```
Decreases LH and FSH release
.
Decreased testosterone
› Decreased sexual drive
› Decreased sperm count
.
Decreased estrogen
› Menstrual irregularities including amenorrhea
› Hot flashes
.
Switch to non-opioid or use buprenorphine
```
36
Pharmacological effects of opioids:
Cardiovascular system
Opioid induced histamine release can lead to peripheral arteriolar and venous dilation => hypotension
CNS depression of vasomotor and adrenergic tone
May result in postural/orthostatic hypotension
.
Morphine is used in patients with dyspnea from pulmonary edema associated with left ventricular heart failure
› Reduced cardiac preload (reduced venous tone) and afterload (decreased peripheral vascular resistance) leading to a decrease in myocardial oxygen consumption
› Dramatically relieves dyspnea associated with pulmonary edema due to LV heart failure
37
Pharmacokinetic of morphine
- Oral absorption undergoes significant first pass metabolism . Equianalgesic dose of morphine is 30mg PO vs. 10mg parenteral
.
- Low lipid solubilityonly 20% is unionized @ plasma pH.
.
- Morphine is metabolized by glucuronideconjunction by CYP2D6.
› Morphine-6-glucuronide is a major active metabolite that is 2X potent as morphine
› Conjugates excreted in urine
› High levels of morphine-3-glucuronide can produce seizures
› With renal impairment, morphine-6-glucuronide accumulates & overdose may result
38
Comparison of opioid analgesics (4 main things to consider)
1. Naturally occurring (morphine, codeine)
2. Partial synthetic (heroin, naloxone)
3. Synthethic (levorphanol, meperidine, methadone)
4. Agonist/antagonist (pentazocine, butorphanol, nalbuphine)
39
Natural and partially synthetic . . . list general
- Codeine
- Heroine
- Oxycodone
- Hydrocodone
- Hydromorphone (dilaudid)
- Apomorphine
- Levorphanol
- Dextromethorphan
40
Natural and partially synthetic
1. Codeine
2. Heroine
1. CODEINE
› Orally active @ 1/10th potency of morphine.
› 10% of codeine metabolized to morphine by CYP2D6
› Anti-tussive at sub-analgesic doses
› Mild analgesic used in combination with ASA or APAP
.
2. Heroine (diacetylmorphine))
› Crosses BBB rapidly due to high lipid solubility
› Metabolized to monoacetylmorphine and morphine which are responsible for
effects of heroin
41
Natural and partially synthetic
3. Oxycodone
4. Hydrocodone
5. Hydromorphone (dilaudid)
3. Oxycodone- Same effects and potency as morphine but has a higher oral activity
4. Hydrocodone - usually formulated with acetaminophen; same effects as morphine, orally active
5. Hydromorphone (dilaudid) - same effects as morphine but with higher oral activity
› 10x more potent than morphine, › Greater respiratory depression
42
Natural and partially synthetic
6. Apomorphine
7. Levorphanol
8. Dextromethorphan
6. Apomorphine- › Has little analgesic activity, does cause respiratory depression, DA agonist activity used to induce vomiting by its direct action @ CTZ
.
7. Levorphanol- › Good oral activity with longer duration of action than morphine with less N/V, Incomplete cross-tolerance with morphine
.
8. Dextromethorphan- D-isomer of codeine analog “methorphan” that has very little
analgesic activity, Antitussive, Less drowsiness or GI disturbances, NMDA antagonist activity may contribute to abuse potential
43
Synthetics opioid . . . general ( 9 in all)
1. Meperidine (Demerol)
2. Propoxyphene
3. Diphenoxylate (Lomotil)
4. Fentanyl
5. Sufentanil (Sufenta)
6. Remifentanil (Ultiva)
7. Tapentadol (Nucynta)
8. Tramadol (Ultram, Ultracet)
9. methadone (Dolophine)
44
Synthetics opioid
| 1.Meperidine (Demerol)
45
Synthetics opioid
2. Propoxyphene
3. Diphenoxylate (Lomotil)
2. Propoxyphene- Same indications and spectrum of activity as codeine.
› d/c in United States in 2011
.
3. Diphenoxylate (Lomotil) - › Formulation contains atropine that can produce
undesirable anticholinergic side effects at supratherapeutic doses
› Only available for PO administration for tx of diarrhea
› Difenoxin (Motofen) is metabolite with similar properties to diphenoxylate
46
Synthetics opioid
| 4. Fentanyl (Sublimaze, Actiq, Duragesic)
47
Synthetics opioid
5. Sufentanil (Sufenta)
6. Remifentanil (Ultiva)
7. Tapentadol (Nucynta)
5. Sufentanil (Sufenta) -Similar to fentanyl in action & use
.
6. Remifentanil (Ultiva)- › metabolized by plasma esterases with an elimination t1/2 of 8-20 minutes. › After 5 hour infusions, full recovery seen in 15 minutes, › Allows for minute by minute control of analgesia
.
7. Tapentadol (Nucynta)- Similar in mechanism of action, efficacy, side effect profile as tramadol
48
Synthetics opioid
| 8. Tramadol (Ultram, Ultracet)
49
Synthetics opioid
| 9. methadone (Dolophine)
50
Methadone maintenance
51
Opioid Antagonist. . . Pure antagonist (drug example)
Naloxone (Narcan)
Naltrexone (Trexan)
Methylnaltrexone (Relistor)
Vivitrol (XR injectable naltrexone)
52
Pure antagonist part 1
| 1. Naloxone (Narcan)
› Naloxone (Narcan): pure competitive antagonist at all opioid receptors with no opioid agonist activity
› No apparent activity of it’s own at therapeutic doses, but will enhance pain in someone who is already in pain
› Short duration of action-approx 1 hour
› Rapid hepatic metabolism (little or no oral activity, must be given parenterally)
› Drug of choice for opioid overdose: 0.4 – 0.8 mg IM or IV for µ agonists, 10-15mg for κ agonist
53
Pure Antagonist part 2
2. Naltrexone (Trexan)
3. Methylnaltrexone (Relistor)
4. Vivitrol (XR injectable naltrexone)
Naltrexone (Trexan): pure competitive opioid antagonist with a 24-hour duration of action.
› Available only in oral formulation
› More potent than naloxone with t1/2 = 3 hours
› Active metabolite 6-naltrexol has t1/2 = 13 hours
.
Methylnaltrexone (Relistor)
› Peripheral action only
› Used to manage constipation in long-term opioid pain treatments
.
Vivitrol (XR injectable naltrexone)
› Treats alcohol and opioid dependence
› 380mg Q4w IM
54
Uses of pure antagonists
```
Treatment of acute opioid overdose
Diagnosis of addiction
Treatment of compulsive opioid use
Treatment of alcoholism (naltrexone)
Treatment of consitpation secondary to long-term opioid treatment (methylnaltrexone)
```
55
Agonist-Antagonist
| Pentazocine (Talwin)
› Analgesic for moderate/severe pain
› Oral and parenterally active
› Weak µ antagonist or partial agonist
Blocks morphine analgesia and induces opioid (mu) withdrawal in physically
dependent patients
Does NOT block morphine respiratory depression
56
Agonist-Antagonist
| Talwin at Agonist @ κ receptors
› Spinal analgesia that is as effective as morphine supraspinal analgesia
› Limited respiratory depression; not as severe as morphine
› Dysphoria, uncontrolled “weird” thoughts & hallucinations esp. with higher doses
› Withdrawal from the physical dependence of pentazocine results in mild morphine-like withdrawal syndrome
› All κ agonist effects are blocked by naloxone
› Talwin NX = combination of pentazocine & naloxone
57
Agonist-Antagonist
| Nalbuphine (Nubain) & Butorphanol (Stadol)
› Analgesic for moderate/severe pain
› Available for injection, butorphanol available as nasal spray
› µ antagonists: antagonize morphine analgesia & will induce abstinence
syndrome in those physically dependent to morphine
58
Agonist-Antagonist
| Nalbuphine (Nubain) & Butorphanol (Stadol) . . . k agonist?
```
κ agonists:
› Produce effective analgesia with limited respiratory depression
› Low incidence of psychomimetic effects
› Mild abstinence syndrome
› Antagonized by naloxone
```
59
Agonist-antagonist . . .
| Buprenorphine (Buprenex)
› Analgesic for moderate/severe pain
.
› Partial agonist @ µ receptors
High affinity for and slow dissociation from µ receptors – slow onset & long lasting effects
Potentially useful replacement for methadone as maintenance drug for opioid abusers.
Induces tolerance to euphoric effects
Partial agonist activity may antagonize the euphoria of street drugs as well as reduce cravings in recovering addicts
.
› Initiate therapy with buprenorphine alone & then maintain with buprenorphine + naloxone (Suboxone)
60
Agonist-antagonist
| Effects of buprenorphine include
```
› Analgesia
› Respiratory depression (different from other µ receptor agonists): as a partial µ agonist, induces only part of the full agonist response. May be a ceiling effect.
› Euphoria
› Mild morphine abstinence syndrome
› κ agonist: clinical use unknown
```
61
Opioid abstinence/ withdrawal
All tolerance to opioids is pharmacodynamic
There is little/no metabolic tolerance
NOT life threatening....Morphine: first sx occur 8-12 h after last dose, peak effects occur @ 36-72 h....Long lasting opioids: symptoms will come & go later; will be less severe
Symptoms similar to severe influenza:
› Diarrhea/vomiting
› Chills/fever/sweating
› Piloerection
› Lacrimation, rhinorrhea
› Yawning, insomnia
.
Protracted withdrawal: anxiety, insomnia & drug cravings can continue for up to 6 months
62
Opioid overdose . . . classic triad of symptoms
1. Depressed respiration
2. Pinpoint pupils
3. Coma
63
Opioid overdose . . .
| Opioid interactions worsen symptoms
```
› Additive or synergistic effects to produce CNS &/or respiratory depression can occur with:
Sedative-hypnotics
Ethanol
MAOI’s
Antihistamines
Tricyclic antidepressants
Antipsychotics
```
