Quiz #3

Question 1

Lateral Motor Systems

Answer 1

1) lateral corticospinal tract:
- origin: primary motor cortex and other frontal and parietal areas
- decussates at the pyramidal decussation - cervicomedullary junction
- is present in entire spinal cord, but most prominent at cervical and lumbosacral regions
- function is movement of contralateral limbs (distal muscles)

2) rubrospinal tract:
- originates at red nucleus, magnocellular division
- decussates at ventral tegmental decussation
- only cervical area
- function is movement of contralateral limbs

Question 2

Medial Motor Systems

Answer 2

1) anterior corticospinal tract:
- orginates in primary motor cortex and supplementatry motor area
- does NOT decussate
- present in cervical and upper thoracic cord
- function is control of bilateral axial and girdle muscles (proximal trunk muscles)

2) vetibulospinal tracts (VSTs):
- originates:
- –medial VST: medial and inferior nuclei
- –laternal VST: lateral VST and lateral vestibular nucleus
- does NOT decussate
- location:
- —medial VST: cerical and upper thoracic
- —lateral VST: entire cord
- function:
- –medial VST: positioning of head and neck
- –lateral VST: balance

3) retirculospinal tracts:
- originate in pontine and meduallry retucular formation
- does NOT decussate
- present in entire cord
- function: automatic posture and gait related movements

4) tectospinal tract:
- originates in superior colliculus
- decusates at the tegmental decussions, in the midbrain
- present in cervical cord
- function: coordination of head and eye movement

Question 3

Upper Motor Neurons

Answer 3

Location: project from the cerebral cortex to the anterior horn of the spinal cord (where they connect with LMNs)

lesions:
- hyperreflexia (spasticity) ,
- muscle weakness
- increased tone

Question 4

Lower Motor Neurons

Answer 4

location: from anterior horn to peripheral nerves

lesions:
- hyporeflexia
- muscle weakness
- fasciculations (muscle twtiches)
- atrophy
- decreased tone

Question 5

buprenorphine

Answer 5

partial mu agonist

Question 6

opioid metabolism

Answer 6

Most opioids are conjugated to glucuronides, which are excreted through the kidney. Morphine is conjugated principally to morphine-3-glucuronide (M3G), which has neuroexcitatory activity mediated through the GABA/glycine system. Accumulation of M3G, for example in renal insufficiency, can result in seizures.

Since the opioids are metabolized by the liver, in patients with liver disease the elimination half-life of morphine is increased. In patients on opioids, ingestion of alcohol can cause major increases in peak serum levels of opioids, particularly hydromorphine and oxymorphine. This is important since alcohol and other drugs such as sedative-hypnotics, antipsychotic agents, antihistamines when used with opioids can produce an additive CNS depression.

Morphine is subject to extensive first pass metabolism, in contrast to codeine which has better oral bioavailability.

Question 7

codeine

Answer 7

Codeine, oxycodone, and hydrocodone are metabolized by the cytochrome P450 isoform CYP2D6 to metabolites with greater potency. For instance, codeine is demethylated to morphine. Genetic polymorphisms in this isozyme are thought to be responsible for variations in the analgesic response of individuals taking codeine. That is, in some individuals less morphine is formed, resulting in less analgesic response; in other individuals, more morphine is formed with the possibility of respiratory depression. Thus, there is much concern about the risk of codeine in children, particularly as a cough suppressant.

Codeine is a useful agent for treating moderate pain without suppressing signs of fever, i.e., it is not antipyretic. Fentanyl would treat moderate pain but is usually used for more severe pain. Aspirin, acetaminophen, and other NSAIDS are all antipyretic and would suppress signs of fever.

Question 8

opioid receptor locations & functions

Answer 8

A major action of opioids is on neurons whose cell bodies lie in the dorsal horn of the spinal cord (i.e., ascending part of the afferent pain transmission pathway to higher cortical centers). Opioids can also act at higher levels on this pathway, including the ventral caudal thalamus.

Opioid receptors can also modulate pain transmission by enhancing descending inhibition to the dorsal horn. Opioids can act at higher levels in this descending pathway, including the rostral ventral medulla and the periaqueductal gray in the midbrain.

Opioid receptors are also located in the medullary chemoreceptor trigger zone in the area postrema, a region around the fourth ventricle responsible for mediating the nausea and vomiting associated with opioid use.

Question 9

opioid mechanism

Answer 9

All opioids have two actions that are thought to mediate their analgesic effects. After binding to the G coupled m-receptor, they inhibit presynaptic voltage-gated Ca2+ channels [why B is wrong and the correct answer], thereby decreasing neurotransmitter release (e.g., glutamate, acetylcholine, norepinephrine, serotonin and substance P). They also hyperpolarize postsynaptic neurons by G protein coupling that opens K+ channels [GIRKs].

As part of their coupling to G proteins, opioids activate phospholipase C and inhibit adenylyl cyclase.

Question 10

opioids side effects

Answer 10

Morphine and other opioids are profoundly constipating, a major complaint of patinets. All the other choices listed are side effects, i.e., nausea and vomiting, pruritis from histamine release, focal myoclonus, and sometimes reduced uterine tone, which can prolong labor.

Question 11

development of new analgesia

Answer 11

There are a number of strategies that could theoretically be used to develop analgesic agents. Inhibiting voltage-gated sodium channels would prevent depolarization of excitatory neurons. Inhibiting presynaptic voltage-gated calcium channels would prevent vesicular release of transmitter.

Agents that inhibit an inhibitory interneuron in the brainstem can result in the activation of pain inhibitory neurons that project from the rostral ventral medulla. Theoretically, inhibiting the post-synaptic NMDA receptor would result in decreased transmission of the pain signal. However, decreasing K+ conductance in a second order pain transmission neuron would result in continued depolarization of the neuron, most likely enhancing pain transmission.

Question 12

tramadol

Answer 12

Tramadol is an analgesic whose primary action is as a serotonin-reuptake inhibitor. It also inhibits norepinephrine reuptake. It has some action as a weak m-receptor agonist. As such, it should be administered with caution in patients who are taking selective serotonin re-uptake inhibitors to avoid precipitation of the serotonin syndrome. As suggested by partial antagonism by naloxone however, activity at the m-receptor is not thought to be the principal mechanism of action. Fortunately, tramadol is free of significant respiratory depression effects. Because of its action on non-opioid receptors, it has some role in the treatment of neuropathic pain. It can cause seizures and thus is relatively contraindicated in patients with epilepsy.

Question 13

opioid OD triad

Answer 13

coma, miosis (pin point pupils), and respiratory depression

Question 14

opioids v NSAIDs

Answer 14

Opioids tend to reduce both the sensory and emotional aspects of pain, whereas NSAIDs have much less effect on the emotional experience of pain. Opioids, however, are less effective in treating neuropathic pain compared with visceral or somatic pain. When tolerance to the analgesic effects of morphine develops, patients can be switched to another opioid to achieve improved analgesia. This is the principle of “opioid rotation.”

NSAIDs are, by and large, equally efficacious and the choice depends on cost, toxicity profile, individual characteristics, and prior history of patient response.

Question 15

opioid use and non-pain related conditions

Answer 15

Opioids can increase smooth muscle tone, which may result in an increase in pain in biliary colic secondary to spasm. The opioid dose can be increased to provide adequate centrally-mediated analgesia. Opioids can also increase the pain due to renal colic, presumably by the same mechanism, i.e., increasing smooth muscle tone. Opioids are very commonly used to reduce pain in patients with burn trauma, myocardial infarction or bone pain from cancer. While other agents may be more effective than opioids in relieving neuropathic pain, opioids are not known to paradoxically increase it.

Morphine and other opioids can suppress respiration leading to an increase in Pco2.The increased level of Pco2 leads to cerebral vasodilation, which decreases cerebral vascular resistance; thereby increasing cerebral blood flow and increasing intracranial pressure. Intracranial pressure elevation in a person with a large brain mass, i.e., a brain tumor, can increase the risk of herniation. Likewise, special caution should be considered in prescribing opioids for pain relief in patients with compromised respiratory function such as asthma or chronic obstructive pulmonary disease.

Morphine is often used to treat pain arising from myocardial infarction. Blood pressure is usually well maintained, but hypotension can occur secondary to peripheral arterial and venous dilation.

Morphine is also used to treat dyspnea from pulmonary edema associated with left ventricular heart failure. It may reduce anxiety (air hunger) and reduce cardiac preload (reduced venous tone) and after load (decreased peripheral resistance).

Opioids have a number of uses apart from pain relief, which include the treatment of cough and diarrhea. Although opioids are respiratory depressants, they are remarkably effective in treating pulmonary edema both for hemodynamic and calming effects. Fentanyl, a potent opioid, is used in anesthesia protocols. Opioids can cause an increase in ureteral tone which actually causes urinary retention.

Question 16

cautionary use with opioids

Answer 16

Opioids are primarily metabolized in the liver; thus individuals who may already be somnolent or stuporous because of hepatic encephalopathy with impaired hepatic function may incur a dangerous buildup of opioids, leading to increased sedation and/or respiratory arrest. Likewise, opioids should be used with caution in patients taking sedating medications such as benzodiazepines, hypnotics, antipsychotic and antidepressant agents.

Opioids are metabolized to the liver to glucuronides that are eliminated through the kidney. Thus, individuals who have renal failure may be unable to eliminate some glucuronides, which if accumulated, may lead to seizures.

Patients with adrenal insufficiency (Addison’s disease) may have an exaggerated prolonged response to opioids. Recall also that opioids can produce hypotension, so use of these drugs in patients with Addison’s disease (mineralocorticoid deficiency) who are predisposed to hypotension can result in marked hypotension. Likewise, caution should be applied for patients in shock or with reduced blood volume. The mechanism of hypotension may involve inhibition of the vasomotor center of the brainstem, inhibition of compensatory baroreceptor reflexes, and increased histamine release.

As opioids can cause respiratory depression, caution is always appropriate when prescribing opioids in patients with pre-existing pulmonary conditions that may involve hypoxemia and/or CO2 retention.

Question 17

meperidine

Answer 17

Meperidine is metabolized to normeperidine, which has a high propensity to cause seizures. The risk that this metabolite will accumulate is greater in patients receiving high doses of morphine or who already have renal failure. High doses can also cause CNS excitation, including tremors, hyperreflexia and delirium.

Most opioids have no major effects on cardiac rhythm, which makes them useful for pain relief in patients with myocardial infarction. They can however produce bradycardia. However, meperidine is noteworthy because it has antimuscarinic actions that can result in tachycardia. (Recall that parathasympathetic actions tend to slow the heart; thus antimuscarinic agents can result in tachycardia.) [Likewise, weak antimuscarinic activity can result in mydriasis, not the expected miosis seen with most opioids.]

Question 18

opioid &tolerance

Answer 18

A high degree of tolerance develops to the central nervous system effects of the opioids, such as sedation, analgesia, and euphoria. In addition, tolerance develops to nausea and vomiting and respiratory depression.

Tolerance is least likely to develop to mioisis and is very slow to develop to constipation. Miosis occurs even in the dark and is mediated by ACh and blocked by atropine.

Tolerance usually develops in individuals exposed to therapeutic doses of opioids about 2-3 weeks later (not 1 week). Tolerance develops more easily with large doses given at small intervals and is less likely to develop with small doses administered over long intervals. The rate at which tolerance develops or ends varies by opioid. For example, tolerance to methadone develops more slowly than to morphine. Moreover, patients who develop tolerance to morphine usually do develop tolerance to other agonist opioids, but the tolerance is often incomplete or partial. This finding underlies the principle of opioid rotation; that is, after effectiveness declines for one type of opioid, an individual can be rotated to another; thereby experiencing improved analgesia at a reduced equivalent dosage. Interestingly, tolerance does NOT develop to the antagonist actions of mixed agents or the pure antagonists. This is fortunate since it allows physicians to administer naloxone repeatedly in cases of opioid overdoses without worry that the individual will be tolerant to the antagonistic actions of naloxone.

The exact mechanism underlying tolerance to opioids is not known. One promising theory is that tolerance arises from a disturbance of the structural interaction between the m receptor and its G proteins, second messenger systems (cAMP) and target ion channels.

Question 19

combination of morphine and phenelzine —> a monoamine oxide inhibitor (MAOI)

Answer 19

the addition of an opioid to an individual on an MAO inhibitor, e.g., phenelzine, can produce a life-threatening serotonin syndrome characterized by neuromuscular hyperactivity, tremor, clonus, myoclonus, and rigidity; autonomic hyperactivity with high fever, and tachycardia; and marked agitation and excitement.

Question 20

aspirin

Answer 20

Aspirin (acetylsalicylic acid, ASA) has analgesic, anti-inflammatory and anti-pyretic effects. It is a non-selective inhibitor of both COX isoforms. It irreversibly inhibits platelet cycooxygenase (COX) and inhibits platelet aggregation, thus making it useful for preventing thrombotic events. However, the same action, which is irreversible, can also result in prolonged bleeding times with an anti-platelet effect (blocks aggregation) that lasts for 8-10 days (i.e., the life of the platelet). This fact is important because physicians often have to tell patients to stop taking aspirin for a week to 10 days before undergoing certain surgical procedures. Aspirin is currently used much more as a prophylactic anti-platelet agent in such conditions as unstable angina and transient ischemic attack, than as an anti-inflammatory agent. Aspirin is hydrolyzed rapidly by esterases in tissue and blood to acetic acid and salicylate. Alkalinization of the urine will increase the rate of excretion of free salicylate and is a useful measure in cases of acute poisoning.

Aspirin is much less commonly used as an anti-inflammatory agent than in the past, and now is more commonly used for its anti-platelet effects. Nonetheless, it can be used in patients with rheumatoid, juvenile, and osteoarthritis.

Adverse effects to aspirin are quite common including nausea, vomiting, diarrhea, dyspepsia, epigastric pain, bleeding and ulceration. Direct chemical effects on gastric cells and a decrease in the production and protective activity of prostaglandins are thought to result in gastric ulcers.

Aspirin hypersensitivity can result in bronchospasm, rhinitis, edema, rash, and anaphylaxis. Aspirin sensitivity is greater in persons with asthma, nasal polyps, and rhinitis.

Aspirin prolongs the bleeding time by irreversibly inhibiting platelet COX-1 and COX-2; it interferes with TXA2 production and suppresses platelet adhesion and aggregation. Thus, it is contraindicated in persons with bleeding disorders such as hemophilia, hypothrombinemia and hepatic disease (vitamin K deficiency).

Use of aspirin for fever control in children with viral syndromes can cause Reye Syndrome, characterized by vomiting, hepatic disturbance, and encephalopathy with high mortality.

Toxicity:
Aspirin intoxication is a medical emergency and can occur in accidental childhood poisonings, suicidal overdoses or accidental overdoses of confused older patients who have chronic pain. At high doses patients experience salicylism with vomiting, tinnitus and vertigo. There is hyperventilation and a respiratory alkalosis secondary to medullary stimulation, followed by a metabolic acidosis. Body temperature rises because of an uncoupling of oxidative phosphorylation. Severe poisoning results in hypothrombinemia, profound metabolic acidosis, seizures, coma, renal and respiratory failure, cardiovascular collapse, and death. Treatment includes immediate supportive care with gastric lavage and charcoal, hydration, intravenous sodium bicarbonate and/or hemodialysis. Always consider ASA poisoning a potential life-threatening emergency.

Question 21

NSAIDs

Answer 21

The anti-inflammatory activity of NSAIDs is thought to be due to NSAIDs’ ability to block cyclooxygenase (COX-1 and COX-2), the enzyme that converts arachidonic acid to prostaglandins. COX-1 is thought to have homeostatic effects and is found in many tissues; COX-2 is induced during inflammation and facilitates the inflammatory response. NSAIDs decrease the sensitivity of the vasculature to bradykinin and histamine, and reverse the vasodilation of the inflammatory response.

NSAIDs are widely used to treat anti-inflammatory conditions such as rheumatoid and osteoarthritis. In addition, they are used to treat mild to moderate pain from headaches and pain arising in integumental and vascular structures, i.e., musculoskeletal pain. The dose used to treat inflammatory conditions is usually much higher than that used for analgesia. NSAIDs also can be used to treat fever. Visceral pain is not as responsive to NSAIDs.

NSAIDs are anti-inflammatory (why they are called non-steroidal anti-inflammatory drugs), pain relieving (i.e., analgesic) and fever reducing (antipyretic). However, the various actions may not all co-occur at low doses. For instance, ibuprofen is analgesic at low doses (<2400mg/day), but is anti-inflammatory only at higher doses.

NSAIDS have similar adverse effects. Most cause abdominal pain and bleeding to some degree. All are potential nephrotoxins, acting to interfere with auto-regulation of renal blood flow, which is influenced by prostaglandins. In high doses used by persons with alcoholism or other underlying liver diseases, they can result in abnormal liver function tests, and on occasion, liver failure. NSAIDs can also cause bronchoconstriction in individuals with asthma. Endocrinopathies, such as hypothyroidism, have to date not been associated with NSAID use.

Question 22

tylenol

Answer 22

Acetaminophen is a non-opioid analgesic, but it has no anti-inflammatory properties. It is therefore not considered an NSAID. It has antipyretic effects and is frequently used to lower fever. It is a common drug for pain relief and often used as a substitute for aspirin in patients with a bleeding diathesis or bronchospasm secondary to aspirin.

Acetaminophen can be dangerous in persons with pre-existing liver disease. (Presumably in this case the patient has some hepatic insufficiency secondary to chronic alcoholism). In normal (non-alcoholic) subjects as little as 15g can be fatal. The principal injury is hepatotoxicity with centrilobular necrosis. Early symptoms of hepatotoxicity include nausea, vomiting, diarrhea, abdominal pain and jaundice. Normally acetaminophen is metabolized by the liver to acetaminophen sulfate and glucuronide. However, its metabolism in high doses results in accumulation of a toxic metabolite, N-acetyl-p-benzoquinone. Hepatic glutathione typically binds the toxic metabolite, but if glutathione is depleted, the toxic metabolite accumulates. Treatment includes administration of acetylcysteine, which acts as a glutathione substitute and binds the toxic metabolite. Always consider acute acetaminophen intoxication a medical emergency.

Acute renal tubular necrosis is another serious complication (option C), but is less common than hepatic failure. Acetaminophen does not have platelet-inhibiting properties (like aspirin) and is less likely to cause gastrointestinal bleeding. Unlike aspirin, it is also less likely to cause bronchospasm.

Question 23

selective COX inhibitors

Answer 23

An advantage of selective COX-2 inhibitors is thought to be the lower probability, compared to non-selective COX inhibitors, of causing gastrointestinal ulcers and bleeds. COX-2 inhibitors have no impact on platelet aggregation. Unfortunately, they have been associated with increased risks of thrombotic events. Moreover, because they inhibit COX-2-mediated prostacycline synthesis in the vascular endothelium, they do not offer cardioprotective effects like traditional non-selective NSAIDs. As COX-2 is active in the kidney, they are associated with renal toxicity to the same degree as traditional NSAIDs. COX-2 inhibitors can also increase the risk of edema and hypertension.

Question 24

mu agonists

Answer 24

Codeine is a partial or weak m-opioid agonist, useful for treating moderate pain. All the others, hydromorphone, fentanyl, oxymorphone and methadone are strong or full m-opioid agonists. Morphine, of course, is the prototype strong or full m-opioid agonist. Morphine, hydromorphine, oxymorphone, methadone and fentanyl are all useful for treating severe pain.

The m-receptor contributes to analgesia, sedation, euphoria, respiratory depression, constipation and physical dependence.

Strong:	
morphine	
heroin	
hydromorphone	
oxymorphone	 
levorphanol	 
fentanyl*	 
methadone	 
meperidine

Weak:
codeine
oxycodone
hydrocodone

Question 25

mu receptor antagonists

Answer 25

The pure m-receptor antagonists are naltrexone, naloxone, and nalmefene. They have a high affinity for the m opioid binding site with a lower affinity for the d and k sites. Naltrexone is often used to reduce craving for alcohol in alcoholics. Naloxone is used primarily to reverse acute opioid overdoses.

Buprenorphine (partial m-agonist, k antagonist), nalbuphine (m-antagonist and strong k agonist) and pentazocine (weak m antagonist/partial m agonist and k agonist) are considered opioids with mixed receptor actions.

k receptors contribute to analgesia, sedation, and miosis. d receptors are thought to contribute to analgesia.

Question 26

types of pain

Answer 26

low threshold - myelinated: fast, pricking pain (ouch)

• fast velocity - A delta fibers
• neospinothalamic pathway

high threshold - unmyelinated axons
- slow, longer lasting, burning/aching pains
slower velocity, groan
- paleoaspinothalamic/spinoreticular pathway