Opioids Flashcards
1
Q
FUNCTIONAL EFFECTS ASSOCIATED WITH OPIOID RECEPTORS
A
- Supraspinal analgesia: μ,κ,δ
- Spinal analgesia: μ,κ,δ
- Respiratory depression: μ
- Reduced GI motility: μ,δ
- Psychotomimesis: κ
- Sedation: μ,κ
2
Q
NEURAL MECHANISMS OF ANALGESIA
A
- inhibit ascending pain transmission.
- Activate descending pain-inhibitory circuits.
- Spinal: Opioids inhibit ascending pain transmission.
- Supraspinal: Pain-inhibitory descending neurons send processes to the spinal cord and inhibit pain transmission neurons.
- The descending pain-inhibitory neurons are inhibited by GABA.
- Opioids inhibit GABAergic neurons.
3
Q
RECEPTOR DISTRIBUTION AND NEURAL MECHANISMS OF ANALGESIA
A
- Usually opioids are given systemically.
- Therefore they act concurrently at both spinal and supraspinal sites.
- Interaction at these sites tends to increase their overall analgesic efficacy.
Peripheral Analgesia
- There are opioid μ receptors on the peripheral terminals of sensory neurons.
- Peripheral administration of opioids,e.g., into the knees of patients undergoing arthroscopic knee surgery, has shown clinical benefit.
4
Q
Meperidine
A
- Mu-opioid agonist
5
Q
Pentazocine
A
- partial mu-agonist or antagonist
- partial kappa-agonist
6
Q
Butorphanol
A
- partial mu-agonist or antagonist
- kappa-agonist
7
Q
Nalbuphine
A
- mu antagonist
- kappa agonist
8
Q
Buprenorphine
A
- partial mu agonist
- kappa antagonist
9
Q
PERIPHERAL EFFECTS
A
Partial list
- Biliary tract: Opioids contract biliary smooth muscle, which may result in biliary colic.
- Genitourinary tract: Renal function is depressed due to decreased renal plasma flow.
- Uterus: May prolong labour. Mechanism unclear.
- Pruritus: Flushing, warming of the skin, sweating and itching.
10
Q
METABOLISM OF OPIOIDS
A
- 10% of morphine is metabolized to morphine-6- glucuronide (M6G).
- M6G is an active metabolite with analgesic potency 4-6 times that of its parent compound.
- M3G and M6G are polar metabolites with limited ability to cross the blood-brain barrier.
- Probably do not contribute significantly to the CNS effects of morphine.
- However,the effects of these metabolites should be considered in patients with renal impairment.
- Esters such as heroin and remifentanil are rapidly hydrolyzed by tissue esterases.
- Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and to morphine, which is then conjugated with glucuronic acid.
- Accumulation of a metabolite of meperidine, normeperidine, may occur in patients with decreased renal function.
- In **high concentrations, normeperidine may cause seizures. **
- Fentanyl is metabolized by CYP3A4 in the liver.
- Fentanyl has no active metabolites; fastest in onset
11
Q
EXCRETION OF OPIOIDS
A
- Polar metabolites, including glucuronide conjugates of opioid analgesics, are excreted mainly in the urine.
- Small amounts of unchanged drug may also be found in the urine.
- Glucuronide conjugates are also found in the bile, but enterohepatic circulation represents only a small portion of the excretory process.
12
Q
USES OF THE OPIOID ANALGESICS
A
Partial list
- Acute Pulmonary Edema: Proposed mechanisms include reduced anxiety, and reduced cardiac preload and afterload.
- Diarrhea: Loperamide and diphenoxylate are the most commonly used drugs to control diarrhea.
13
Q
CONTRAINDICATIONS AND CAUTIONS
A
PATIENTS WITH HEAD INJURIES
- CO2 retention caused by respiratory depression results in cerebral vasodilation.
- In patients with elevated ICP, this may lead to lethal alterations in brain function.
PATIENTS WITH ENDOCRINE DISEASE: Patients with adrenal insufficiency or hypothyroidism may have prolonged and exaggerated responses to opioids.
14
Q
DRUG INTERACTIONS
A
Partial list
Antipsychotics
- Increase sedation.
- Variable effects on respiratory depression.
- Accentuation of CV effects (antimuscarinic and α-blocking actions).
MAO inhibitors
- concurrent use of meperidine and an MAOI has resulted in excess 5HT & has resulted in a potentially life-threatening reaction in several patients.
- Similar interactions have been seen when tramadol was taken with MAOIs.
15
Q
HYDROMORPHONE AND OXYMORPHONE
A
- Strong agonists useful in treating severe pain.
- Rapidly hydrolyzed to 6-MAM, which, is then hydrolyzed to morphine.
- Both heroin and 6-MAM are more liposoluble than morphine and enter the brain more readily.
- Morphine and 6-MAM are responsible for the pharmacological actions of heroin.
16
Q
MEPERIDINE
A
- Strong μ receptor agonist.
- No longer recommended for treatment of chronic pain due to concerns over metabolite toxicity.
- meperidine short T1/2 but metabolite has long T1/2
- Large doses of meperidine repeated at short intervals produce tremors, muscle twitches, dilated pupils, hyperactive reflexes and convulsions.
- These symptoms are due to the accumulation of the metabolite normeperidine, which has a half- life of 15-20 hours compared with 3 hours for meperidine. -> not suitable for routine dosing
DRUG INTERACTIONS
- The most prominent is an excitatory reaction (“serotonin syndrome”) with delirium, hyperthermia, headache, hyper- or hypotension, rigidity, convulsions, coma, and death.
- Due to the ability of meperidine to block reuptake of serotonin.
- Meperidine should not be used in patients taking other serotonergic agents such as MAO inhibitors.
17
Q
FENTANYL
A
- STRONG μ agonist.
- Rapid onset and short duration of action (15-30 minutes).
- The fentanyl subgroup also includes sufentanil, alfentanil, and remifentanil.
- Fentanyl is 100 times more potent than morphine, and sufentanil is 1000 times more potent than morphine.
- Alfentanil is seldom used.
18
Q
METHADONE
A
- Approximately equal in potency to morphine.
- Induces less euphoria and has a longer duration of action.
- Methadone is a μ receptor agonist, an NMDA receptor antagonist, and a serotonin and norepinephrine reuptake inhibitor.
- These multiple mechanisms of action make methadone an interesting choice for chronic pain.
Adverse
- QT prolongation, torsades de pointes and death have been reported with methadone.
- A related compound, levomethadyl acetate, which has an even longer half-life than methadone, has been approved by the FDA for use in detoxification clinics.
19
Q
DEXTROPROPOXYPHENE
A
- MILD TO MODERATE μ agonist
- Weaker analgesic than codeine.
- Often used in combination with acetaminophen.
- Propoxyphene has an increased risk of seizures and cardiac conduction abnormalities and should be avoided in the elderly.
20
Q
TRAMADOL
A
- Weak μ agonist and norepinephrine and serotonin reuptake inhibitor.
- Useful in neuropathic pain. ex. diabetic neuropathy
- Tramadol is associated with an increased risk of seizures in patients with a seizure disorder and those taking medications that lower seizure threshold.
- Use of tramadol with other serotonergic drugs should be avoided because it may precipitate a serotonin syndrome.
21
Q
PENTAZOCINE, BUTORPHANOL, NALBUPHINE & BUPRENORPHINE
A
- MIXED AGONIST-ANTAGONISTS:
- The mixed opioid agonist–antagonists are potent analgesics in opioid-naive patients.
- They precipitate withdrawal in patients who are physically dependent on opioids.
- Useful in mild to moderate pain.
- They were developed to reduce the addiction potential of the opioids.
- Pentazocine is a κ agonist and a μ antagonist or partial agonist.
- Butorphanol is a κ agonist and a μ antagonist or partial agonist.
- Nalbuphine is a κ agonist and a μ antagonist.
- Buprenorphine is a partial μ agonist and a κ antagonist.
- Buprenorphine is approved for the management of opioid addiction.
- Mixed agonist-antagonists are not recommended as routine analgesics, because they have ceiling effect.
Adverse
- Also, pentazocine, butorphanol and nalbuphine may cause psychotomimetic effects.
- Psychotomimetic effects are uncommon with buprenorphine.
22
Q
DIPHENOXYLATE
A
- ANTIMOTILITY AGENTS
- Widely used in the treatment of diarrhea.
- They act by several different mechanisms, mediated principally through either μ or δ receptors on enteric nerves, epithelial cells, and muscle.
- At the usual doses, diphenoxylate and loperamide lack analgesic effects
