pharmacology- opioids Flashcards
3 categories that non intravenous opioids fall into
Clinically relevant non intravenous opioids can be categorized into three structural groups: naturally occurring alkaloids, semi synthetic alkaloids, and synthetic opioids.
natural alkaloids (morphine and codeine)
semi synthetics (hydromorphone, hydrocodone, oxycodone, oxymorphone and bupenorphine).
synthetic (methadone, fentanyl, tramadol, tapendadol)
why is codeine considered to be a natural occurring opioid despite being manufactured?
Although the majority of codeine available worldwide is manufactured from morphine as a semisynthetic alkaloid, codeine is found naturally along with morphine in the poppy seed.
what are the oral semi synthetic alkaloid opioid agents?
Semisynthetic alkaloids include hydromorphone (Dilaudid), hydrocodone (Norco, Vicodin), oxycodone (Percocet, Oxycontin), oxymorphone (Opana), and buprenorphine (Suboxone, Subutex). These drugs are derived from morphine, typically with substitutions of ester, hydroxyl, keto-, or methyl groups at the 3 and 6 carbon or 17 nitrogen positions of morphine.
what are the sub classifications of synthetic opioids?
ynthetic opioids are further characterized as phenylheptylamines, including methadone, and phenylpiperidines, including fentanyl. Tramadol and tapentadol are also included in this group.
What is the mechanism of action for opiod agents?
Simple- Opioids produce their primary effects by interacting with opioid receptors. Existing in three distinct types (i.e., µ, κ, and δ), these receptors are coupled with G proteins that, when activated by drugs or endogenous ligands (e.g., β-endorphins), produce inhibitory effects that hyperpolarize the cell and thereby attenuate nociceptive impulses.
All opioids exert their primary pharmacologic effects by interactions with opioid receptors at multiple sites in the central nervous system (CNS). The classic µ, κ, and δ opioid receptors (described by international nomenclature as MOP, KOP, and DOP for mu, kappa, or delta opioid peptide) are typical G-protein–coupled receptors. Binding of the opioid leads to an overall reduction in neuronal excitability via membrane hyperpolarization as the result of decreased cyclic adenosine monophosphate production, decreased calcium ion influx, and increased potassium ion efflux.
Tramadol and tapentadol are unique among nonintravenous opioids in that they bind to opioid receptors, but they also exert an analgesic effect through inhibiting reuptake of serotonin and norepinephrine; tramadol primarily inhibits serotonin reuptake and tapentadol primarily inhibits norepinephrine reuptake.
Fentanyl also inhibits serotonin reuptake, although the contribution to its clinical analgesic effect is unclear.
How are opioids metabolised?
The majority of nonintravenous opioids are metabolized by the cytochrome P450 system, primary via the 3A4 and 2D6 isoforms. Notable exceptions include morphine, hydromorphone, and oxymorphone. Morphine is chiefly metabolized via glucuronidation to the metabolites morphine-3-glucuronide (M3G), which has CNS neuroexcitatory effects, and morphine-6-glucuronide (M6G), an analgesic 50 times more potent than morphine. Hydromorphone and oxymorphone are the cytochrome P4502D6 metabolites of hydrocodone and oxycodone, respectively. They undergo glucuronidation as well as some reduction. Less is known about the activity of their metabolites, although hydromorphone-3-glucuronide may have CNS neuroexcitatory effects.
Most opioids are metabolized to inactive metabolites, although some, such as tramadol and codeine, are prodrugs that require metabolism to an active metabolite for clinical effect. Morphine is again a notable exception in having active metabolites.
What is the time to peak concentration, duration of effect and half life of oxycodone?
there are both short acting and extended release formulations of oxyycodone.
Short acting- time to peak, 1-1.5 hours, duration 2-4 hours, t half life 3.5 hours
extended release- time to peak, 4.5-5 hours, duration 12 hours, t half life 3.5 hours.
Describe the pharmacokinetics of transdermal opioid patches.
Fentanyl and buprenorphine are unique because transdermal delivery systems enable continuous delivery. Modern transdermal patches use an inert polymer matrix impregnated with dissolved drug that has evolved from early transdermal systems that consisted of a simple drug reservoir separated by a rate-limiting membrane.
Drug delivery with transdermal patches is a result of the concentration gradient between the patch and skin, is proportional to the area of exposed skin, and allows for a near zero-order delivery of medication at steady state without being subject to first-pass metabolism. This reduces, though does not eliminate, variability in serum opioid concentration. Additionally, this gradient is in part temperature-dependent, with increased absorption occurring at higher temperatures. Serious adverse effects and deaths have occurred with concurrent application of external heat, such as with electric heating blankets, saunas, and hot tubs.
What are some of the common drug interactions with opioid medications?
1) CNS depressants can lead to profound sedation, respiratory depression, and death, particularly with gamma aminobutyric acid (GABA) A agonists such as benzodiazepines, barbiturates, propofol, and alcohol. These interactions are synergistic.
2) drugs with significant anticholinergic activity can induce Opioid-associated urinary retention and constipation.
3) serotonergic medications. Of particular clinical significance is the increased incidence of constipation in the setting of concomitant use of opioids and ondansetron owing to the effect of ondansetron on serotonin-mediated gastrointestinal peristalsis. Constipation is a common adverse effect associated with ondansetron, occurring in nearly 10% of patients treated for nausea and vomiting associated with chemotherapy, and can be worsened by opioid therapy in this patient population.
The synthetic opioids, including fentanyl, methadone, tramadol, and meperidine, are all weakly serotonergic and have been implicated in multiple reports of serotonin syndrome when used in combination with other serotonergic medications such as monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants, and lithium.
4) drugs metabolised by the cytochrome P450 system, particularly CYP2D6 and CYP3A4. These enzymes are affected not only by allelic variations but also by many other medications that act as substrates, inhibitors, and inducers. Common inducers include anticonvulsant agents and pentobarbital. Calcium channel blockers, selective serotonin reuptake inhibitors, benzodiazepines, many psychotropic agents, and multiple antibiotics act as both a substrate and an inducer of CYP 450 enzymes, and many opioids have substantial interaction potential with these commonly used agents.
describe the use and the considerations for opioids in renal insufficiency.
The liver is the major site for biotransformation and elimination of most opioids; however, the majority of opioid metabolites are renally cleared. Although these metabolites are often inactive or minimally active, an important exception is morphine. Morphine is metabolized to the inactive metabolite M3G and the active analgesic metabolite M6G, which has an analgesic potency near that of morphine. Accumulation of M6G leading to respiratory depression in patients with altered renal clearance mechanisms constitutes the basis for avoiding morphine therapy in patients with renal failure. Because codeine is metabolized to morphine it should also be avoided in patients with renal insufficiency.
Oxycodone and oxymorphone both have active metabolites. In uremic patients the elimination half-life is lengthened and excretion of metabolites is impaired; however, the clinical relevance of this is largely unstudied in the setting of renal insufficiency.
Tramadol produces the metabolically active metabolite M1, and an increased dosing interval of 12 hours is recommended in patients with compromised renal function.
Fentanyl, methadone, and buprenorphine are considered safe in patients with renal insufficiency and do not require dose adjustment. Hydromorphone is also a preferred opioid in patients with renal impairment, although it has a potentially active metabolite. In the setting of dialysis, hydromorphone levels are reduced to 40% of predialysis levels, whereas fentanyl and buprenorphine are not dialyzable and levels remain unchanged following dialysis.
Describe the considerations for the use of opioids in hepatic impairment
The liver is the major site of metabolism for most opioids; thus patients with liver disease who require opioid treatment present unique challenges. Impaired liver function not only leads to changes in the pharmacokinetic properties of drugs but can also lead to alteration in plasma protein binding and the plasma concentration of unbound “free” drug.
This altered drug disposition can lead to increased therapeutic effect and an increase in adverse effects, potentially manifest as sedation, respiratory depression, and potentiation of hepatic encephalopathy. Unfortunately, there is limited data to guide specific dosing recommendations of opioids in the ambulatory setting in patients with liver failure.
Because their metabolites are inactive, fentanyl and hydromorphone are often the preferred agents in patients with liver disease. However, lower starting doses, slower dose titration, and increased dose intervals are recommended when initiating ambulatory therapy with any of the commonly used opioids in patients with significant hepatic insufficiency. Limited data exists for buprenorphine, although it has been used without adverse effect in patients with concurrent liver dysfunction owing to hepatitis C and, with caution and close monitoring, appears to be safe in patients with liver disease.
what are some of the considerations for the use of opioids in the elderly?
Advanced age is known to be an important covariate that alters both the pharmacokinetic and pharmacodynamics properties of opioids. In general, opioid clearance is lower and opioid potency is greater in the elderly.
Compared with younger patients, a given dose produces higher plasma concentrations and more pronounced effects, both therapeutic and adverse, in the older patient.
Among elderly patients falls, fractures, sedation, and impaired cognition dominate concerns about the use of opioids. Unpredictable or greater than expected opioid effects can result from age-related reduction in renal function, drug-drug interactions owing to use of multiple prescription medications, and overall increased frailty in this population. Opioids as a class have been associated with an increased risk of falls and fractures and it does not appear that one opioid is vastly superior to another, although there is a lower incidence of fractures with transdermal buprenorphine compared with other opioids.
In terms of selecting a specific opioid for elderly patients it appears that transdermal fentanyl and transdermal buprenorphine are generally safe and well-tolerated, with a lower incidence of constipation. The transdermal route, with infrequent need to change patches, also increases compliance. Transdermal buprenorphine (available in the United States) offers the advantage of a low dosage option (the 5-µg/hr patch is equivalent to approximately 15 mg of oral morphine over 24 hours) for the elderly patient. It is prudent to avoid morphine in the elderly to avoid M6G accumulation in patients with unrecognized, age-related renal impairment. All opioid analgesics in the elderly should be started at lower doses, with increased dosing intervals and slower up-titration with close monitoring of the therapeutic response and side effect proflie.
What is the property of codeine metabolism that can effect its overall effect?
Codeine is a prodrug that requires conversion by Cytochrome P450 2D6 (CYP2D6) in the liver to its active metabolites, codeine-6-glucuronide and morphine, that are ultimately responsible for codeine’s analgesic effects. Patients with diminished or absent CYP2D6 activity have limited response to codeine, whereas patients who are ultrarapid metabolizers (e.g., CYP2D6 gene duplications) can have exaggerated responses to codeine owing to more extensive metabolism to morphine.
describe some of the properties of oxycodone
Oxycodone is a semisynthetic opioid synthesized from the opiate alkaloid thebaine. It is available in short-acting and extended-release formulations as well as preparations compounded with acetaminophen or aspirin. Oxycodone undergoes low first-pass metabolism and has a higher bioavailability (60%-87%) compared with morphine. It undergoes O -demethylation via both CYP3A4 and CYP2D6 to oxymorphone, its primary active metabolite, which is three times more potent than morphine. Oxycodone also undergoes metabolism by CYP3A4 to noroxycodone, which has weak µ-opioid receptor activity compared with oxycodone or oxymorphone.
It has been suggested that individuals with decreased CYP2D6 activity because of genetic polymorphisms require higher doses of oxycodone as the result of lower oxymorphone production, but there is limited evidence to support this assertion.
Oxycodone and its metabolites primarily undergo urinary excretion with less than 10% of the parent compound excreted unchanged.
Describe the properties of Tramadol
Tramadol is a weak µ-receptor agonist and exerts additional central-acting analgesic effects via serotonin reuptake inhibition (and norepinephrine to a lesser degree). It is considered a weak opioid and is recommended for the treatment of mild to moderate pain.
Tramadol undergoes extensive metabolism by CYP2D6 and CYP3A4 as well as glucuronidation. The primary pharmacologically active metabolite is O-desmethyltramadol (M1) formed by CYP2D6.
Tramadol is thus affected by genetic polymorphisms of CYP2D6. Tramadol and M1 both exert analgesic effects, although M1 is a more potent µ-receptor agonist, and tramadol itself is a more potent serotonin-norepinephrine reuptake inhibitor.
Tramadol and its metabolites are excreted in the urine with 30% excreted unchanged.
Because of this unique serotonin reuptake inhibition, clinicians must be aware of the potential for serotonin syndrome if tramadol is combined with monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, tricyclic antidepressants, or other serotonergic medications. Short-acting and extended-release oral formulations are available in the United States as well as a combination tablet with acetaminophen.
describe the chemical structure of opioids
he opioids of clinical interest in anesthesiology share many structural features. Morphine, the principal active compound derived from opium, is a benzylisoquinoline alkaloid; the benzylisoquinoline structural backbone is present in many important naturally occurring drugs including papaverine, tubocurarine, and morphine. Morphine’s benzylisoquinoline based structure is shown in Fig. 17.1 . Many commonly used semisynthetic opioids are created by simple modification of the morphine molecule. Codeine, for example, is the 3-methyl derivative of morphine. Similarly, hydromorphone, hydrocodone, and oxycodone are also synthesized by relatively simple modifications of morphine. More complex alteration of the morphine molecular skeleton results in mixed agonist-antagonists such as nalbuphine and even pure competitive antagonists such as naloxone.
Some of the morphine derivatives have chiral centers and thus are typically synthesized as racemic mixtures of two enantiomers; only the levorotatory enantiomer is significantly active at the opioid receptor. The naturally occurring, stereospecific enzymatic machinery in the poppy plant produces morphine only in the levorotatory form.
The fentanyl series of opioids are chemically related to meperidine. Meperidine is the first completely synthetic opioid and can be regarded as the prototype clinical phenylpiperidine. As shown in Fig. 17.1 , fentanyl is a simple modification of the basic phenylpiperidine structure found within meperidine; the other commonly used fentanyl congeners such as alfentanil and sufentanil are somewhat more complex versions of the same phenylpiperidine skeleton. As these drugs have no chiral center and therefore exist in a single form, the pharmacologic complexities of stereochemistry do not apply
Describe the physicochemical and pharmacokinetic parameters of morphine
Describe the physicochemical and pharmacokinetic parameters of fentanyl
Describe the physicochemical and pharmacokinetic parameters of sufentanyl
Describe the physicochemical and pharmacokinetic parameters of alfentanyl
Describe the physicochemical and pharmacokinetic parameters of remifentanyl
describe the different types of opioid receptors and the differences in clinical effect.
Additionally there is receptor subtypes (e.g., µ-1, µ-2, and so on) though it is not clear from molecular biology techniques that distinct genes code for them. Posttranscriptional and posttranslational modification of opioid receptors certainly occurs and could be responsible for conflicting data regarding opioid receptor subtypes. It is well known, for example, that the messenger RNA coding for the human µ-receptor undergoes alternative splicing, resulting in subtle differences in the final receptor.
Studies in genetically altered mice have yielded important information about opioid receptor function. In µ-opioid receptor knockout mice, morphine induced analgesia, reward effect, and withdrawal effect are absent. Fig. 17.4 demonstrates the simple power of these site-directed mutagenesis techniques, confirming how MOR knockout mice exhibit no analgesic effect to morphine as assessed by measuring the time to jumping off a hot plate. Importantly, MOR knockout mice also fail to exhibit respiratory depression in response to morphine.
describe the main enzymes involved in opioid drug metabolism.
describe and compare the bolus front and back end kinetics of fentanyl, morphine and remifentanyl.
Describe the front and back end kinetics of IV opioid infusions for fentanyl, morphine and remifentanyl
Describe the effect of opioids on the ventilatory response to Pa CO2
an increase in arterial carbon dioxide partial pressure dramatically increases the minute ventilation. Under the influence of opioid analgesics, the curve is flattened and shifted to the right such that at a given carbon dioxide partial pressure the minute ventilation is lower. More importantly, the “hockey-stick” shape of the normal curve is lost such that under the influence of µ-agonists there may be a partial pressure of carbon dioxide below which the patient does not breathe (this point can be thought of as the “apneic threshold”). µ-agonists also depress the hypoxic drive to breathe, although this effect is less important clinically than the effect on carbon dioxide–controlled ventilatory drive.
What is the issue with morphine in kidney failure?
Morphine is principally metabolized by conjugation in the liver; the resulting water-soluble glucuronides (i.e., morphine 3-glucuronide and morphine 6-glucuronide [M3G and M6G] are excreted via the kidney. The kidney also plays a role in the conjugation of morphine and may account for as much as half of its conversion to M3G and M6G.
M3G is inactive, but M6G is an analgesic with a potency rivaling morphine. Very high levels of M6G and life-threatening respiratory depression can develop in patients with renal failure.
