Opiod Receptors and Endogenous peptides Flashcards
Four broad classes of opiod receptors are currently accepted.
Most clinically important pharmacologic effects of opiod alkaloids are mediated by which receptors?
μ, κ, and δ receptors
The 4th receptors is called the nociception-orphanin FQ (NOP) receptor - may also be invovled in pain processing
Which receptors mediate the classic classical pharmacological effects of morphine?
What are these classical effects of morphine
μ receptors
The classic effects are analgesia and ventilatory depression
There are many subclasses of μ receptors and what do they mediate
μ1 - supraspinal analgesia
μ2 - ventilatory depression and spinal analgesia
μ3 - vascular control and immune modulation (on leukocytes)
Although genetic polymorphisms exist, most receptor variants are a result of posttranscriptional or posttranslational modifications
μ receptors are encoded by which gene?
What explains the variability seen in how patients respond to opiods
OPRM1, found on Chr 6q24-q25.
Although genetic polymorphisms exist, most receptor variants arise from posttranscriptional or posttranslational modifications. The transcribed
mRNA may be modified by splicing or polyadenylation, whereas the receptor may be covalently modified by phosphorylation or conjugation to ubiquitin.
More than 20 μ-receptor variants have been identified and cloned. This heterogeneity explains.
- Why opioids have variable efficacy and toxicity in different patients
- It may also account for the fact that patients who are tolerant to the effects of one μ agonist can sometimes get relief with another.
Which opiod receptors is responsible for the dysphoria effect of opiods?
The κ receptors
- These receptors are encoded by a single gene but can theoretically produce at least 6 mRNA variants
Which κ receptors respond to analgesics that are used clinically and what are their effects?
κ1 receptor - spinal analgesia
κ3 receptor - supraspinal analgesia, sedation, and
ventilatory depression
What is the most prevalent opiod receptor in the brain and what does it do?
κ3 receptor which results in supraspinal analgesia, sedation, and ventilatory depression
Which receptor is responsible for mediating some of the analgesic effects of endogenous opiod peptides, especiall in the spinal cord?
δ receptor
Only a few clinically opiods have affinity for this receptor at usual analgesic doses
If a μ-selective opioid is administered in a sufficiently high dose (to treat a tolerant patient, for example), the drug may be less selective and produce significant δ effects
What kind of receptors are opiod receptors?
These are G-protein couple receptors
-All have 7 transmembrane domains and significant structural homology
What is the overal action of actions of both μ and δ agonists?
They result in overal neuronal depression
They share several signal transduction
mechanisms, including:
- Inhibition of adenylyl cyclase,
- Activation of K+ currents - hyperpolarizes postsynaptic neuronal membranes and reduce their responsiveness
- Suppression of Ca2+ currents - this prevents the release of neurotransmitters involved in pain like Substance P in the pre-synaptic cell
Other mechanisms have been demonstrated, including stimulation of phospholipase C and mitogen-activated protein kinase, as well as blockade of calcium channels. The κ receptor elicits similar cellular responses, and it may also block calcium channels.
What are the five families of endogenous opiods?
EPPPE - 5 of them
Enkephalins
Dynorphins
Beta-endorphin (most important)
Orphanin FQ
Endomorphins
What are enkephalins?
What are they derived from?
What opiod receptor are they selective for?
Where are enkephalins found?
These are endogenous peptides derived from proenkephalin A
Selective for δ receptors
Act as neurotransmitters released from short interneurons within the spinal cord and brainstem.
They are found in the adrenal medulla and in nerve
terminals that contain catecholamines.
What is the structure of proenkephalin A (the molecule that gives rise to enkephalins)?
Each molecule of proenkephalin contains:
- Four sequences of met-enkephalin (Tyr-Gly-Gly-Phe-Met),
- One copy of leu-enkephalin (Tyr-Gly-Gly-Phe-Leu)
- Some slightly larger enkephalin-like peptides
What is the enkephalins mechanism of action?
Enkephalins (and exogenous opioids) bind to presynaptic opioid receptors on nociceptive neurons and modulate the release of various pain neurotransmitters.
The naturally occurring enkephalins are hydrolyzed extremely rapidly by peptidases in plasma. Stable analogues of the enkephalins have been synthesized, permitting in vivo experiments on their actions.
What are dynophins and what are they derived from?
Which receptors are they selective for?
Where are they found?
These are endogenous opiods. There is dynorphin A and B both from Prodynorphin (aka proenkephalin B)
Dynorphins show selectivity for the κ receptor
Just like enkephalins - They are found in the adrenal medulla and in nerve
terminals that contain catecholamines.
The 5 amino acids at the N-terminus
of the dynorphins are identical in sequence to leu-enkephalin.
What is propriomelanocortin (POMC)?
Where is it found?
What important opiod does it form (what receptor does this opiod affect)
Selectve cleavage of POMC can also give what hormones?
It is a protein that contains a multitude of opiod and nonopiod peptides
It is found in high concentration in the anterior pituitary and the hypothalamus
Side note: The N-terminus of POMC is identical to met-enkephalin, although POMC is not cleaved to yield met-enkephalin.
β-endorphin (formed from the final 31 amino acids) - is the most important of the humoral endogenous opioids, and an important endogenous ligand at the μ receptor.
Selective cleavage of POMC yields many nonopioid hormones including:
- Adrenocorticotropic hormone (ACTH),
- Several varieties of melanocyte stimulating hormone (MSH),
- Lipotropins.
What is orphanin FQ aka nociceptin
Why is it the orphan?
What is its mechanism of action?
Where is it found in the body?
What are its effects?
This is a peptide containing 17 amino acids derived from the cleavage of Proorpphanin
Although proorphanin has significant sequence
homology with the other 3 parent opioid peptides, orphanin FQ does not bind to μ, κ, or δ receptors –> it is the orphan of the endogenous opiods.
Mechanism: It binds to a G-protein coupled receptor (NOP) and causes cellular responses similar to other opioids, including inhibition of adenylyl cyclase, opening of the inwardly rectifying potassium channel, and blockade of calcium channels.
Found in the hippocampus and sensory cortex
Effects
- Supraspinal antianalgesic effect while producing spinal analgesia
What are endomorphins
What are the types and the receptors they affect?
What are the cardiovascular effects (centrally and peripherally)
They are endogenous agonists that have high affinity and high selectivity for the μ receptor.
A precursor molecule for the endomorphins has not yet been identified.
- The tetrapeptide Tyr-Pro-Trp-Phe-NH2 is called **endomorphin-1 ** –> acts via stimulation of μ2 receptors
- peptide, Tyr-Pro-Phe-Phe-NH2, is called endomorphin-2 –> less specific, acting at both μ and κ receptors.
These peptides have both in vitro and in vivo cardiovascular effects:
- They decrease spontaneous neuronal discharge in the rostral ventrolateral medulla (RVLM), an area important in the central control of blood pressure.
- Peripherally, they decrease norepinephrine release from vascular sympathetic neurons.
What is the physiological role of morphine:
Immunomodulatory or Analgesic?
The physiologic role of morphine is more likely to be immunomudulatory
Mammals have the ability to synthesize morphine from tyrosine precursors, using the same reaction scheme as the opium poppy. The significance of
endogenous morphine is unknown, but it is interesting that arthritic rats make more morphine than do healthy ones. The concentration of endogenous morphine is too low to activate μ1 or μ2 receptors, but its concentration is within the range that activates μ3 receptors on lymphocytes. This finding indicates that its physiologic role is more likely to be an immunomodulator rather than an analgesic.
What was the described role of COX-1
What are the major roles of prostaglandins made from COX-1
COX-1 role
- platelet adhesiveness
- protection of the gastrointestinal tract against damage from acid
These are expressed in most tissues
Prostaglandins made from COX-1 major roles:
- nociception
- GI mucosal intergrity
- glomerular filtration rate
- platelet TXA2 synthesis
What was the described role of COX-2
What are the major roles of prostaglandins made from COX-2 (8)
Role - mediated the synthesis of prostaglandins that participated in the inflammatory response
Expression of COX-2 is can be stimulated by various growth factors, tumor promoters, hormones, bacterial endotoxin and cytokines.
Prostaglandins made from COX-2 major functions:
- Inflammation
- Resolution of inflammation
- GI adaptive cytoprotection
- Renal sodium balance
- Kidney development
- Angiogenesis
- Endothialial PGI2 synthesis
- Protection against myocardial ischemic damage
Physiologically, what do prostaglandins do?
- Produce an increased sensitivity of peripheral nociceptors resulting in hyperalgesia
- They also produce a central hyperalgesic action at the level of the dorsal horn of the spinal cord
What is required for maximal antinociceptive activity?
Inhibition of both both COX-1 and COX-2
Similarly, inhibition of either of them can decrease the ability of the GI mucosa to protect itself from acid mediated damage
Do COX-1 inhibitor delay or promote bone healing
COX-1 inhibitors delay bone healing in both humans and rats.
This adverse effect is not seen with selective COX-2 inhibitors
IIbuprofen
Mechanism?
Effects on GI and platelets
Inhibits both COX-1 and COX-2 reversibly
Less GI toxicity compared to asprin
Platelet inhibition is of short duration and platelet function returns to normal after stopping drug
Available OTC and also in combination with hydrocodone
Asprin
It is also known as…?
Mechanism?
What’s asprin’s effect as an analgesic, antiinflammatory, antipyretic and also as an antiplatelete agent and how long do these effect last for each?
Acetylsalicylic acid
Inhibits COX-1 and is not an inhibitor of COX-2 at therapuetic concentrations.
Asprin results in permanent inhiibition of the COX-1 enzyme, however, new synthesis occurs rapidly–> its analgesic, antiinflammatory, antipyretic effects are the same duration as ibuprofen
Asprin effects on platelets is still siginificant because platelets do not carry out protein synthesis –> there will be significant increase in bleeding time for about a week.
Celecoxib
Mechanism?
Inhibits COX-2 only
Defined by its lack of ability to inhibit platelet thromboxane sythesis
Compare and contrast the analgesic effects of COX inhibitors and that produced by opiods
- There is no ceiling effect with opiods –> An adequate dose, individually titrated for a particular patient, will relieve virtually any
pain. However, ventilatory depression and sedation. VS COX inhibitorrs that can reach their ceiling effect in patients wtih severe pain - Since opioids have no intrinsic antiinflammatory effects, COX inhibitors work particularly well when the source of the pain has an inflammatory component.
- COX inhibitors decrease the requirements for opiods when given concomitantly (ie. there is an opiod sparing effect)
If a patient is still feeling pain after being given COX-inhibtors, opiods should be added to the regimen
There may be theoretical advantage in combining acetamenophen with another COX inhibitor in therapy
What are the GI effects of asprin and how are they divided?
Divided into those that occur rapidly and those that require day to weeks to manifest
Rapid effects - due to both central and peripheral actions:
- Heartburn
- nausea
- vomiting
Later effects:
- Ulcers - can result in painless bleeding –> vomiting blood and melanotic stools
High dose asprin can cause what side effect
How is this made better
What other side effects can you expect with asprin?
Asprin
This is reversible upon discontinuation of the drug
Prostaglandins mediate renal vasodilation. Thus, asprin decreases sodium excretion and may precipitate acute renal failure in a patient who renal perfusion is dependant upon critical level of prostaglandins
A hypersensitivity reaction can occur to asprin. Patients with a history of asthma, nasal polyps, or urticaria –> manifestations can be as minor as rhinorrhea or resemble a full blown anaphylactic reaction although mechanism is not immunologic.
-An explanation for this is that when COX is inhibited arachidonic acid is preferentially converted to leukotrienes that mediate the asthma, nasal polyps and urticaria
People having having such a reaction to COX inhibitor should avoid all other COX inhibitors except for acetaminophen
What part of asprin is responsible for the covalent bond that irreversibly inhibits COX
The acetyl group
There are numerous preparations that contain salicylic acid that reversibly inhibits COX. These compounds are used for what?
This compunds are used as anti-inflammatory agents and not usually used as analgesics
Acetaminophen
In what way does it differ with asprin?
Mechanism?
Effects on platelets, GI, and renal system
Similar to asprin in terms of its analgesic and antipyretic effects
It differs from asprin in that it has little, if any, antiinflammatory activity.
Acetaminophen at a given concentration inhibits both COX-1 and COX-2 to the same degree, however the degree of inhibition is only about 50% at the highest clinical concentrations. It therefore has no adverse effects referable to inhibition of COX-1 or COX-2 such as platelet inhibition, gastrointestinal ulceration, or renal impairment.
Which COX inhibitor can be given in the third trimester of pregnancy?
Acetaminophen - because it does not cause premature closure of the ductus arteriosus
Whats a significant side effect that can result from acetaminophen overdose?
What’s the maximum daily dose?
Fatal hepatic necrosis
Daily dose should not exceed 4g - it is important to calculate the total dose from all sources
Acetaminophen and another COX inhibitor given
concomitantly may produce superior analgesia to either medication given alone.
Naproxen
It is similar to ibuprofen in that it has a longer duration and may be given twice a day
Ketorolac
How is it unique
Compare and contrast IV vs IM routes of administration as far as onset, length of effect
What guideline is recommended to prevent toxicity?
What is the most prominent side effect even with 5 days of therapy?
What’s another side effect seen with this drug
Selective for COX-1
* It is an effective alternative to opiods that could be given parenterally
The IM route has a slower onset with peak plasma concentration occuring about an hour after the infection as compared to 1-2 mins following IV
The IM routes also result in a more prolonged effect, potentially increasing the dosing interval
An oral tablet form (10mg) is also available
In order to minimize severe toxicity, the use of ketorolac by any route should generally not exceed firve days
The incidence of GI ulcers is high even with just 5 days of therapy
Ketorolac delays bone healing in rats
What is the COX inhibitor that is reliably substituted for morphine in some subjects with significant pain
Ketorolac
In persons requiring opioids for postoperative pain management, the concurrent administration of ketorolac resulted in a decreased use of opioids by patient-controlled analgesia typically by 50%.
Indomethacin
Additional effects?
Use?
Used for its anti-inflammatory effect - its a nonselective COX inhibitor
In addition to COX, it also:
- Inhibits the motility of polymorphonuclear leukocytes
- Depresses the biosynthesis of mucopolysaccharides
- Vasocontrictor
Becuase of these additional effects, it has a higher efficacy than other COX inhibitors
Celecoxib
First drug marketed as a selective COX-2 inhibitor
Because its absorption from the gastrointestinal tract is slow and the time to the peak effect is a few hours, celecoxib was marketed for the management of arthritis but not for acute pain.
Diclofenac
Selective for the COX-2 inhibitor
Etodolac
Selective COX-2 inhibitor
What warning are given with COX inhibitors on the drug
“may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.”
This label is given to both COX-1 and COX-2 inhibitors which doesnt make sense. Why?
Inhibition of COX-2 causes the “bad” cardiovascular effects of inhibiting the synthesis of PGI2 (an endogenous anticoagulant) and prostaglandins that are endogenous coronary vasodilators. In contrast, inhibition of COX-1 inhibits the synthesis of TXA2 (that mediates platelet stickiness). From a cardiovascular point of view, inhibition of COX-1 is “good” while inhibition of COX-2 is “bad.” Considering all COX inhibitors as equivalently bad is silly.
Why is dose of asprin prevent to prevent heart attacks only 81mg?
At a dose of 81 mg, virtually all of the ingested dose is metabolized in the liver and the circulating concentration of aspirin is near zero. This allows the aspirin to “kill” platelets as they transit through the liver without producing inhibition of the synthesis of PGI2 (an endogenous anticoagulant) in the systemic circulation. Higher doses of aspirin (e.g., 325 – 500 mg) do achieve systemic concentrations that can inhibit synthesis of PGI2. This is a rare example in pharmacology of a biphasic dose-response curve; at low doses, aspirin has an anticoagulant effect, while the overall anticoagulant effect diminishes at higher doses of aspirin.
What kind of pain does not respons well to opiods and COX inhibitors?
Neuropathic pain
What do neuropathic patients usually respond to for pain?
“Atypical analgesics” such as medications used primarily as antidepressants or anticonvulsants
What are the most commonly used “atypical” analgesics?
amitriptyline - tricyclic antidepressant
carbamazepine - anticonvulsant
gabapentine - anticonvulsant
Amytriptyline
Tricyclic antidepressant used as an atypical analgesic for neuropathic pain
Carbamezipine
anticonvulsant used as an atypical analgesic for neuropathic pain
Gabapentine
anticonvulsant used as a atypical analgesic for neuropathic pain
