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How do opioid agonist work?

Produce analgesia by activating receptors located primarily in the brain and spinal cord regions involved in transmission and modulation of pain


What are the three major receptors that have been identified in various nervous system sites and other tissues?

--G protein linked receptors, coupled to inhibition of adenylyl cyclase activation of receptor operated K channels and suppression of voltage operated Ca channels


Analgesia, euphoria, respiratory depression and physiological dependence result mainly from activation of what receptors?



Delta and Kappa receptors also contribute to analgesia, particularly at what level?

Spinal level


Mixed agonist-antagonist compounds, with agonist selectivity for the kappa receptor, were developed in the hope that?

Less addictive potential and respiratory depression than morphine and other related drugs
A ceiling effect occurs that limits the amount of analgesia attainable with these drugs


Some mixed agonist-antagonist drugs such as what?

Pentazocine, butorphanol and nalbuphine
-cause severe psychotomimetic effects that are not reversible with naloxone
These drugs also can precipitate withdrawal in opioid tolerant patients


What are the functional effects and their associated receptor?

Supraspinal Analgesia: mu, kappa and delta
Spinal Analgesia: mu, kappa, delta
Respiratory depression: mu
Reduced GI motility: mu and delta
Psychotomimesis: kappa
Sedation: mu and kappa


Opioids have two well established actions on neurons, what are they?

1. Close voltage gated channels on presynaptic nerve terminals and therefore reduce neurotransmitter release
2. Open K+ channels thus hyperpolarizing and inhibiting postsynpatic neurons
--both reduce neurotransmitters like: glutamate, AcH, NE, serotonin and substance P.


First up lets discuss spinal analgesia. Mu, delta and Kappa receptors are present in the dorsal horn of the spinal cord. Receptors are present on both spinal cord pain transmission and presynaptically on the primary afferents that relay the pain message to them. How do opioids work then?

1. Opioids inhibit release of excitatory neurotransmitters (substance P and glutamate) from these primary afferents
2. Opioids also directly inhibit the dorsal horn pain transmission neuron.


Next is supraspinal analgesia. How does supraspinal pain work?

Pain-inhibitory descending neurons send processes to the spinal cord and inhibit pain transmission neurons
Pain inhibitor descending neurons are activated by opioids
--this activation results from the inhibition of inhibitory neuron by opioids


How are opioids given?

--so to act concurrently at both spinal and supraspinal sites
--interaction at these sites tends to increase their overall analgesic effect


Last is Peripheral Analgesia, there are opioid mu receptors on the peripheral terminals of sensory neurons. How do opioids work on these receptors?

Stimulation of peripheral mu receptors by opioids decreases sensory neuron activity and transmitter release
--peripheral administration of opioids has shown some benefit


What are the classifications of opioid analgesics?

1. Pure agonist: most of the typical morphine like drugs, all have high affinity for mu receptors
2. Partial and mixed agonist-antagonist: combine a degree of agonist and antagonist activity
3. Antagonist: naloxone and naltrexone


What are the pure agonist drugs?

Morphine (mu = strong and delta/kappa= weak)
Fentanyl (mu = strong)
Meperidine (mu=strong)
Methadone (mu=strong)
Codeine (mu = weak and delta = weak)


What are the mixed agonist-antagonist?

Pentazocine (mu = partial or antagonist and kappa = agonist)
Butorphanol (mu = partial or antagonist and kappa = agonist)
Nalbuphine (mu = antagonist and kappa = agonist)
Buprenorphine (mu = partial and kappa = antagonist)


What are the antagonist?

Naloxone (mu, delta and kappa = antagonist)
Naltrexone (mu, delta and kappa = antagonist)


What are the CNS effects of opioids?

1. Analgesia: decrease emotional component of pain
2. Euphoria: floating sensation with less anxiety
3. Sedation and drowsiness
4. Respiratory depression: reduction of responsiveness of the brainstem respiratory centers to CO2
5. Cough suppression: depress cough reflex by a direct effect on a cough center in the medulla
6. Miosis: Excitatory action on the parasympathetic nerve innervating the pupil
7. Truncal rigidity: action at supraspinal levels
8. N/V: Activate the brainstem chemoreceptor trigger zone


What are the peripheral effects of opioids?

1. Hypotension: inhibit the vasomotor center in the brainstem causing vasodilation
2. GI tract: constipation through the action of local enteric nervous system
3. Biliary tract: contract biliary smooth muscle
4. Uterus: prolong labor
5. Neuroendocrine: stimulate release of ADH, PRL and somatotropin by inhibit release of LH
6. Pruritus: flushing, warming of skin, sweating and itching


Opioids are converted to polar metabolites (glucuronides) and then what?

excreted by the kidneys


How is morphine metabolized?

Conjugated to morphine-3-glucuronide (M3G) (and 10% to M6G)
--neuroexcitatory properties that are not mediated by opioid receptors
--polar metabolites with poor BBB diffusion
--effects of these active metabolites should be considered in patients with renal impairment


How are esters such as heroin and remifentanil metabolized?

Hydrolyzed by common tissue esterases.
--heroin is hydrolyzed to monoacetylmorphine and finally to morphine


Accumulation of a metabolite of meperidine or normeperidine, may occur in patients with decreased renal function. In high concentrations, normeperidine can cause?



How is fentanyl metabolized?

Metabolized by CYP3A4 in the liver


How are codeine, oxycodone and hydrocodone metabolized?

Metabolized in the liver by CYP2D6
--production of metabolites of greater potency
Codeine is demethylated to morphine


How are opioids excreted?

Mainly in the urine
Glucuronide conjugates are found in the bile


Moving on to clinical uses of opioid analgesics. What are some clinical uses?

1. Analgesia: treatment of relatively constant moderate to severe pain
2. Acute Pulmonary edema: (morphine) relieves SOB caused by Pulmonary edema with LVF. Also use for treated pain due to MI with pulmonary edema
3. Cough: antitussives (Dextrometorphan and codeine)
4. Diarrhea: Loperamide and Diphenoxylate are most commonly used
5. Pre-Med before surgery due to sedative, anxiolytic and analgesic properties
6. Intraoperatively: usually in CVS surgeries or other high risk surgery with the goal of cardiovascular depression
7. Regional Analgesics for epidurals or subarachnoid spaces


What are adverse effects of opioids?

1. N/V
2. Sedation
3. Itching
4. Constipation
5. Urinary retention
6. Hypotension
7. Resp depression


Explain the tolerance, dependence and addition aspects of opioid use.

--gradual loss of effectiveness so therefore tolerance
--occurrence of a withdrawal or abstinence syndrome when the drug is stopped (common)
--euphoria, indifference to stimuli, and sedation usually caused by opioid analgesics tend to promote their compulsive use (not as common)


What are some contraindications and cautions with opioid therapy?

1. Giving a weak partial agonist to a patient receiving a partial agonist there is a risk of diminishing analgesia or even inducing withdrawal
2. Head Injuries: alteration in brain function; CO2 retention caused by respiratory depression results in cerebral vasodilation
3. Pregnancy: fetus may become physically dependent in utero and will manifest withdrawal symptoms
4. Impaired pulmonary function: depressant properties can lead to resp failure
5. Impaired hepatic function: metabolized in liver
6. Impaired renal function: half life is prolonged in patients with renal failure; metabolites may accumulate
7. Endocrine disease: adrenal insufficiency or hypothyroidism may have prolonged effects


What are some drug interactions with opioids?

1. Sedative-hypnotics: increase CNS depression
2. Antipsychotics: increase sedation
3. MAO inhibitors: concurrent used with meperidine and an MAOI has resulted in life threatening reactions -- muscle rigidity, hyperthermia and unconsciousness.
--similar effects have been seen with tramadol and MAOIs

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