Pharmacology Iii - Exam 2

Front 1

What are the endogenous analgesic peptides?

Back 1

Enkephalins
Endorphins
Dynorphins

Front 2

How are they classified and what are the differences among classes?

Back 2

Classified via peptide type / length.
Enkephalins – pentapeptides widely distributed in CNS, especially interneurons of pain pathways. In adrenal medulla and GIT.
Endorphins – β endorphin: 31 residue peptide; in hypothalamus and anterior pituitary; derived from protein containing ACTH. ACTH and β endorphin co-released in response to stress.
Dynorphins – peptides of varying lengths widely distributed in CNS, especially interneurons of pain pathways.

Front 3

Do they interact with opioid receptors? Is their action antagonized by naloxone?

Back 3

These interact with all opioid receptors. Naloxone antagonizes their action.

Front 4

Binding of opioids to post-synaptic cause ________.

Binding to pre-synaptic receptors _______.

Back 4

1) Hyperpolarization
2) reduces the release of excitatory NT such as substance P

Front 5

Pain is decreased by which pathway?

Back 5

Binding inhibits adenylate cyclase --> dec. cAMP --> dec. Calcium conductance --> Inc. Potassium conductance --> inhibition of NT release

Front 6

What are the types of opioid receptors and what actions are mediated by each type?

Back 6

Mu (μ) – mediates supraspinal analgesia, constipation, dose-dependent respiratory depression, euphoria, and physical dependence. Miosis too. Pre-and post-synaptic.

Kappa (κ) – mediates spinal analgesia, less miosis and respiratory depression than mu receptors, and dysphoria and disorientation; located pre-synaptic.

Delta (δ) – actions these receptors mediate in man are unclear; in animals, mediate supraspinal and spinal analgesia. Located pre-synaptic.

Front 7

What is the MOA and analgesic effects of morphine?

Back 7

acts preferentially on mu receptors; decreases the activity of neurons in the CNS and GI tract; exhibits pre-synaptic actions (decreased excitatory neurotransmitter release) and post-synaptic (hyperpolarization). Analgesic effects: potent analgesia; occurs without loss of consciousness or loss of sensory input (touch, vision, hearing); reduction in pain sensation as well as reduction in the reaction to pain; continuous dull pain relieved more effectively than sharp intermittent pain (relieved at higher doses).

Front 8

What are the effects of morphine on the medulla?

Back 8

Depression of respiratory center in the medulla;
decreased response to CO2.
Dose-dependent and dose-limiting (general cause of death);
depression of all phases of respiration (rate, volume);
may cause irregular breathing at therapeutic doses (Cheyne-Stokes respiration);
increased CO2 causes cerebral vasodilation (increases intracranial pressure)

Front 9

What are the effects of morphine on CTZ?

Back 9

Stimulates CTZ to cause nausea and vomiting; vestibular stimulation also occurs affecting ambulatory patients more b/c moving around

Front 10

What are the effects of morphine on CV system?

Back 10

Insignificant effects on the myocardium; causes peripheral vasodilation, leading to reduced peripheral resistance (indirect effect due to the morphine-induced release of histamine)

Front 11

What are the effects of morphine on GI tract?

Back 11

Markedly decreases propulsive contractions in small and large intestines; resting tone is increased with periodic spasms occurring; secretion of fluid and electrolytes into the lumen is decreased.

Front 12

What are the differences between morphine and meperidine?

Back 12

Meperidine is 7.5-10 fold less potent than morphine. Meperidine doesn’t stimulate CTZ so decreased N/V unless pt is ambulatory b/c vestibular apparatus stimulated. Meperidine has no antitussive activity, morphine depresses medullary cough center. Meperidine is less effective at reducing propulsive contractions, less constriction of bile duct sphincter (decreased likelihood of constipation and biliary tract spasm). Meperidine has toxic metabolite, normeperidine which produces CNS excitation (tremors, muscle twitches, and seizures). Meperidine inhibits serotonin reuptake. Meperidine is useful in obstetric procedures (lower potential for causing fetal respiratory depression); not useful as antitussive or antidiarrheal, but high abuse potential b/c not as many GI side effects as morphine. At equi-analgesic doses: extent of sedation, euphoria, and respiratory depression is similar to morphine.

Front 13

What are the differences between morphine and codeine?

Back 13

Codeine – methyl derivative of morphine. Higher oral:parenteral ratio (60% vs 25%). Less analgesic, emetic and respiratory depressant activity, similar antitussive activity, lower abuse potential; low affinity for mu receptors; 120 mg of codeine = 10 mg of morphine (additive analgesic effects when combined).

Front 14

What are the differences between morphine and hydromorphone?

Back 14

Derivative of morphine; 7-11X more potent as an analgesic and respiratory depressant; exhibits less miosis, emesis, and sedation than morphine.

Front 15

What are the differences between morphine and oxycodone?

Back 15

Derivative of codeine; high oral:parenteral ratio; used for treatment of moderate-to-severe pain, often in combination with NSAIDs

Front 16

What are the differences between morphine and methadone?

Back 16

Therapeutic effects similar to morphine: analgesic activity, miotic activity, respiratory depressant activity, antitussive activity, and antidiarrheal activity; different form morphine: oral effectiveness as an analgesic (not given parenterally often), long duration of action, and slow development of therapeutic actions.

Front 17

What are the differences between morphine and tramadol?

Back 17

Tramadol – analgesic MoA: 1) binding to mu-opioid receptors and 2) inhibition of reuptake of NE and serotoning in the periphery. 6000 fold lower affinity for the mu receptor than morphine; analgesic activities partially antagonized by naloxone (means 2nd MoA is providing analgesic effect); analgesic activity is 10-20% that of morphine; causes much less respiratory depression than morphine; causes CNS depression and inhibition of GI tract motility similar to that of morphine. Lower potential for abuse and dependence; risk of seizures in patients taking SSRI’s, MAOI’s, TCA’s, or antipsychotics.

Front 18

What are the differences between meperidine and loperamide?

Back 18

Loperamide = meperidine derivative. 1000 fold lower dose required for antidiarrheal action than for CNS effects (poorly absorbed; low abuse potential); major side effect is cramping

Front 19

What are the differences between Tapentadol and tramadol?

Back 19

Tapentadol – analgesic MoA: 1) mu agonism and 2) antagonism of NE reuptake. More potent than tramadol. Increased risk for seizures in patients taking antidepressants and antipsychotics. Lower potential for drug interactions than tramadol (lack of metabolism by CYP3A4 and 2D6; dependence and abuse develop. Schedule 2.

Front 20

What are the differences between naloxone and naltrexone?

Back 20

Naltrexone – pure opioid antagonist with higher oral efficacy and a longer duration of action than naloxone. Chronic use of naltrexone associated with headaches and elevation in serum transaminase levels. Used for maintenance of former opioid addicts in opioid free state, tx of infant apnea syndrome, and alcoholism therapy

Front 21

What is the difference between pentazocine and butorphanol?

Back 21

Pentazocine – weak mu antagonist and kappa agonist. Produces spinal analgesia, sedation, and respiratory depression; respiratory depression (via kappa receptors) is not dose-dependent at higher doses (ceiling effect; like BNZs vs BARs). At therapeutic doses, less GI tract actions than morphine-like agonists. At high doses, dysphoria, disorientation, increase in blood pressure. Weak mu antagonist: minimal antagonism of analgesic actions of morphine given acutely; may precipitate abstinence syndrome in physically dependent subjects on morphine-like agonists. SE’s include sedation, sweating, dizziness, and nausea. Tolerance and physical dependence can develop with repeated use. Lower abuse potential than morphine-like agonists. Tx = chronic severe pain (oral and parenteral administration). Butorphanol – actions and side effects similar to pentazocine (kappa agonist); less mu antagonist activity; neither precipitates nor suppresses an abstinence syndrome in subjects physically dependent upon morphine-like opioid drugs. Tx = relief of acute severe pain.

Front 22

What is the difference between pentazocine and buprenorphine?

Back 22

Buprenorphine – partial agonist at mu receptors. Precipitates or suppresses the abstinence syndrome in subjects physically dependent on opioid drugs; abrupt discontinuation of buprenorphine precipitates mild abstinence syndrome. SE’s = sedation, N&V, dizziness, sweating, and headache. Use = relief of moderate-to-severe pain (parenteral administration) and for maintenance of opioid addicts during opioid withdrawal (oral administration)

Front 23

What are the differences and similarities between hydrocodone and oxycodone?

Back 23

Similarities – both are derivatives of codeine structurally, often in combination w/ NSAIDs
Differences – Hydrocodone: metabolized to hydromorphone by CYP2D6, used for moderate pain, antitussive, and most commonly prescribed in US. Oxycodone – high oral:parenteral ratio, used for moderate-to-severe pain; frequently abused.

Front 24

What is the role of CYP2D6 in the analgesic actions of codeine? Are ultrarapid metabolizers more or less susceptible to codeine toxicity than rapid metabolizers? What about slow metabolizers relative to rapid metabolizers?

Back 24

CYP2D6 metabolizes codeine to morphine. Ultrarapid metabolizers are more susceptible to codeine toxicity than rapid metabolizers. Slow metabolizers will not get the analgesic effects of codeine as quickly as rapid metabolizers.

Front 25

What are the mechanisms underlying the analgesic actions of methadone? What are the therapeutic advantages resulting from the non-opioid actions of methadone?

Back 25

Methadone – potent mu agonist; antagonist at NMDA receptors; blocks reuptake of serotonin and NE. Effective orally for analgesic, miotic, respiratory depression, antitussive, and antidiarrheal activity. Non-opioid actions cause long duration of action and slow development of tolerance to therapeutic actions so given as tx of opioid abstinence syndrome and tx of subjects addicted to opioids.

Front 26

What is the expected effect of chronic administration of a mu agonist?

Back 26

Produces a reduced effect (tolerance). Dependence = the requirement for the continuous presence of an agonist to prevent a withdrawal syndrome

Front 27

Administration of a 2nd mu agonist to a subject undergoing withdrawal from a mu agonist?

Back 27

Suppresses the onset of withdrawal syndrome

Front 28

Administration of a kappa agonist to a subject undergoing withdrawal from a mu agonist?

Back 28

No effect on withdrawal from mu agonist.

Front 29

Administration of a mu antagonist to a subject physically dependent on a mu agonist?

Back 29

Precipitates a withdrawal syndrome

Front 30

Administration of a mu antagonist to a normal subject?

Back 30

Drug specific side effects appear????

Front 31

Why does meperidine cause interactions with MAO inhibitors?

Back 31

Thought to inhibit reuptake of serotonin which leads to excitation, delirium, hyperpyrexia, and convulsions (Serotonin Syndrome)

Front 32

What are the uses of fentanyl?

Back 32

Surgical anesthesia (of particular benefit in cardiac surgery; parenteral); tx of chronic, severe pain (transdermal preparations). 100-1000X more potent than morphine w/ peak action in 5 minutes.

Front 33

What are the mechanism of action and uses of naloxone? Why does it precipitate a severe, abrupt withdrawal syndrome in subjects physically dependent upon morphine-like agonists?

Back 33

Pure antagonist of mu, kappa, and delta receptors. Used as drug of choice for opioid antagonism; therapy for opioid overdose (particularly to antagonize respiratory depression), in diagnosis of physical dependence on opioids, and as deterrent for opioid addiction; disadvantages: effective by parenteral route only and short duration of action (high 1st pass). IV administration prevents or promptly reverses the effects of morphine-like agonists and precipitates a moderate-to-severe, abrupt (within minutes) abstinence syndrome in subjects who are physically dependent on opioid agonists; increases plasma levels of LH, FSH, and ACTH by antagonizing actions of endogenous analgesic peptides. Minimal SE’s expected unless administered subsequent to morphine-like agonists or under conditions which endogenous analgesic peptides are released (stress, shock); no abuse potential.

Front 34

Why may buprenorphine either precipitate or suppress a withdrawal syndrome in subjects physically dependent upon a mu agonist such as morphine?

Back 34

Buprenorphine – partial agonist at mu receptors; precipitates or suppresses the abstinence syndrome in subjects physically dependent on opioid drugs (mu agonists only); abrupt discontinuation precipitates a mild abstinence syndrome.

Front 35

What are the therapeutic indications for narcotic analgesics?

Back 35

Therapeutic indications: treatment of acute moderate-to-severe pain that cannot be relieved by NSAIDs; pre-operative and post-operative analgesia.

Front 36

What property limits the use of opioid analgesics in chronic pain?

Back 36

Tolerance and dose dependence should limit use of opioid analgesics in chronic pain.

Front 37

What are the therapeutic indications for opioid analgesics in chronic pain?

Back 37

For moderate pain: codeine, tramadol, hydrocodone
For severe pain: morphine, oxycodone, hydromorphone,fentanyl, methadone

Front 38

What are the alternatives/adjuncts to opioids for non-terminal chronic pain?

Back 38

For non-terminal conditions: alternative therapy should be maximized before opioid use: NSAIDs, NSAIDs in combination with codeine or opioid agonist/antagonist, TCA/duloxetine, pregabalin/gabapentin, topicals (capsaicin, lidocaine, salicylates), local nerve blocks, acupuncture, cognitive therapy
For terminal disease, opioid analgesics should be utilized aggressively